Pyranylphenyl naphthalene lactones as inhibitors of leukotriene biosynthesis

ABSTRACT

Compounds having the formula I: ##STR1## are inhibitors of leukotriene biosynthesis. These compounds are useful as anti-asthmatic, anti-allergic, anti-inflammatory, and cytoprotective agents. They are also useful in treating angina, cerebral spasm, glomerular nephritis, hepatitis, endotoxemia, uveitis and allograft rejection and in preventing the formation of atherosclerotic plaques.

CROSS-REFERENCE

This is a continuation of application Ser. No. 07/834,921 filed Feb. 13,1992, which is a CIP of U.S. Ser. No. 804,132, Dec. 6, 1991, nowabandoned, which is a continuation of U.S. Ser. No. 662,534, Feb. 28,1991, now abandoned.

The hydroxyacid forms of the present lactones are the subject of aco-pending U.S. patent application U.S. Ser. No. 834,912, filed on evendate herewith, which is incorporated herein by reference.

BACKGROUND OF THE INVENTION

The leukotrienes constitute a group of locally acting hormones, producedin living systems from arachidonic acid. The major leukotrienes areLeukotriene B₄ (abbreviated at LTB₄), LTC₄, LTD₄ and LTE₄. Thebiosynthesis of these leukotrienes begins with the action of the enzyme5-lipoxygenase on arachidonic acid to produce the epoxide known asLeukotriene A₄ (LTA₄), which is converted to the other leukotrienes bysubsequent enzymatic steps. Further details of the biosynthesis as wellas the metabolism of the leukotrienes are to be found in the bookLeukotrienes and Lipoxygenases, ed. J. Rokach, Elsevier, Amsterdam(1989). The actions of the leukotrienes in living systems and theircontribution to various diseases states are also discussed in the bookby Rokach.

EP 375,404 (Jun. 27, 1990) describes certain naphthalene-containingheterocyclic ethers of structure A which are inhibitors of the enzyme5-lipoxygenase. EP application 375,452 (Jun. 27, 1990) describesnaphthalene-containing hydrocarbon ethers of structure B which arereported to possess the same activity. Both of these series of compoundsdiffer significantly from the present invention in that they lack boththe aryl substituent and the additional fused ring of the presentcompounds. A series of natural products known as the justicidins arereferred to in the Merck Index, 11th edition, 1989, no. 5154. Thejusticidins differ considerably from the present compounds in that theyare lacking the large pyranylphenyl group. ##STR2##

SUMMARY OF THE INVENTION

The present invention relates to pyranylphenyl naphthalene lactoneshaving activity as leukotriene biosynthesis inhibitors, to methods fortheir preparation, and to methods and pharmaceutical formulations forusing these compounds in mammals (especially humans).

Because of their activity as leukotriene biosynthesis inhibitors, thecompounds of the present invention are useful as anti-asthmatic,anti-allergic, anti-inflammatory, and cytoprotective agents. They arealso useful in treating angina, cerebral spasm, glomerular nephritis,hepatitis, endotoxemia, uveitis and allograft rejection and inpreventing the formation of atherosclerotic plaques.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of the present invention may be represented by thefollowing formula I: ##STR3## wherein: R¹ and R⁵ are independently H,OH, lower alkyl, or lower alkoxy;

R² is H, lower alkyl or together with R¹ forms a double bonded oxygen(═0);

R³ is H, lower alkyl, or together with R¹ forms a carbon bridge of 2 or3 carbon atoms, said bridge optionally containing a double bond;

each R⁴, R⁶ and R⁷ is independently H or lower alkyl;

R⁸ is halogen, lower alkyl, or lower alkoxy;

each R⁹ is independently H, halogen, lower alkyl, or lower alkoxy;

R¹⁰ is H, halogen, lower alkyl, or lower alkoxy;

X¹ is O, S, S(O), S(O)₂ or CH₂ ;

X² is N, N(O), C(OR⁷) or C(R⁷);

X³ is CH₂ O, OCH₂, or CH₂ CH₂ ;

○Ar is phenyl or 1- or 2-naphthyl;

m is 0, 1 or 2;

n is 1 or 2;

or the pharmaceutically acceptable salts thereof.

The compounds of Formula I are preferably administered in thehydroxyacid form, which can be prepared by treating the lactones hereinby methods known in the art such as with a strong base. Discussionsherein of dosages, compositions, combinations with other drugs, etc. canbe applied to said hydroxyacid form.

Definitions

The following abbreviations have the indicated meanings:

Ac=acetyl

Bn=benzyl

i-Pr=isopropyl

n-Pr=normal propyl

n-Bu=normal butyl

i-Bu=isobutyl

s-Bu=secondary butyl

t-Bu=tertiary butyl

Et=ethyl

Me=methyl

Ph=phenyl

RIA=radioimmuno assay

TFAA=trifluoroacetic anhydride

AIBN=azoisobutyronitrile

LDA=lithium diisopropylamide

DMSO=dimethylsulfoxide

Ts=p-toluenesulfonate=tosylate

Ms=methanesulfonate=mesylate

Et₃ N=triethylamine

DMF=N,N-dimethylformamide

Tf=trifluoromethanesulfonyl

DHP=dihydropyran

DIPHOS=1,2-bis(diphenylphosphino)ethane

DMAP=4-dimethylaminopyridine

NBS=N-bromosuccinimide

THP=tetrahydropyran

PCC=pyridinium chlorochromate

Alkyl is intended to include linear and branched structures andcombinations thereof.

"Alkyl" includes "lower alkyl" and extends to cover carbon fragmentshaving up to 20 carbon atoms. Examples of alkyl groups include octyl,nonyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, eicosyl,3,7-diethyl-2,2-dimethyl-4-propylnonyl, and the like.

"Lower alkyl" means alkyl groups of from 1 to 7 carbon atoms. Examplesof lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl,s- and t-butyl, pentyl, hexyl, heptyl, and the like.

"Lower alkoxy" means alkoxy groups of from 1 to 7 carbon atoms of astraight, branched, or cyclic configuration. Examples of lower alkoxygroups include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy,cyclohexyloxy, and the like.

Halogen means F, Cl, Br, and I.

It is intended that the definitions of any substituent (e.g., R⁴, R⁷,etc.) in a particular molecule be independent of its definitionselsewhere in the molecule. Thus, --(CR⁵ R⁶)₂ -- represents CH₂ CH₂,CH(CH₃)CH₂, C(CH₃)₂ CH(CH₃), etc.

Optical Isomers-Diastereomers-Geometric Isomers

Some of the compounds described herein contain one or more asymmetriccenters and may thus give rise to diastereomers and optical isomers. Thepresent invention is meant to comprehend such possible diastereomers aswell as their racemic and resolved, enantiomerically pure forms andpharmaceutically acceptable salts thereof.

Salts

The pharmaceutical compositions of the present invention comprise acompound of Formula I as an active ingredient or a pharmaceuticallyacceptable salt, thereof, and may also contain a pharmaceuticallyacceptable carrier and optionally other therapeutic ingredients. Theterm "pharmaceutically acceptable salts" refers to salts prepared frompharmaceutically acceptable non-toxic bases including inorganic basesand organic bases. Salts derived from inorganic bases include aluminum,ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganicsalts, manganous, potassium, sodium, zinc, and the like. Particularlypreferred are the ammonium, calcium, magnesium, potassium, and sodiumsalts. Salts derived from pharmaceutically acceptable organic non-toxicbases include salts of primary, secondary, and tertiary amines,substituted amines including naturally occurring substituted amines,cyclic amines and basic ion exchange resins, such as arginine, betaine,caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine,2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine,glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine, and the like.

When the compound of the present invention is basic, salts may beprepared from pharmaceutically acceptable non-toxic acids, includinginorganic and organic acids. Such acids include acetic, benzenesulfonic,benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic,glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic,mandelic, methanesulfonic, music, nitric, pamoic, pantothenic,phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid and thelike. Particularly preferred are citric, hydrobromic, hydrochloric,maleic, phosphoric, sulfuric and tartaric acids.

It will be understood that in the discussion of methods of treatmentwhich follows, references to the compounds of Formula I are meant toalso include the pharmaceutically acceptable salts.

Utilities

The ability of the compounds of Formula I to inhibit biosynthesis of theleukotrienes makes them useful for preventing or reversing the symptomsinduced by the leukotrienes in a human subject. This inhibition of themammalian biosynthesis of leukotrienes indicates that the compounds andpharmaceutical compositions thereof are useful to treat, prevent, orameliorate in mammals and especially in humans: 1) pulmonary disordersincluding diseases such as asthma, chronic bronchitis, and relatedobstructive airway diseases, 2) allergies and allergic reactions such asallergic rhinitis, contact dermatitis, allergic conjunctivitis, and thelike, 3) inflammation such as arthritis or inflammatory bowel disease,4) pain, 5) skin disorders such as psoriasis, atopic eczema, and thelike, 6) cardiovascular disorders such as angina, formation ofatherosclerotic plaques, myocardial ischemia, hypertension, plateletaggregation and the like, 7) renal insufficiency arising from ischaemiainduced by immunological or chemical (cyclosporin) etiology and 8)migraine or cluster headache, 9) ocular conditions such as uveitis, 10)hepatitis resulting from chemical, immunological or infectious stimuli,11) trauma or shock states such as burn injuries, endotoxemia and thelike, 12) allograft rejection, 13) prevention of side effects associatedwith therapeutic administration of cytokines such as Interleukin II andtumor necrosis factor, 14) chronic lung diseases such as cysticfibrosis, bronchitis and other small- and large-airway diseases, 15)cholecystitis, and 16) multiple sclerosis.

Thus, the compounds of the present invention may also be used to treator prevent mammalian (especially, human) disease states such as erosivegastritis; erosive esophagitis; diarrhea; cerebral spasm; prematurelabor; spontaneous abortion; dysmenorrhea; ischemia; noxiousagent-induced damage or necrosis of hepatic, pancreatic, renal, ormyocardial tissue; liver parenchymal damage caused by hepatoxic agentssuch as CCl₄ and D-galactosamine; ischemic renal failure;disease-induced hepatic damage; bile salt induced pancreatic or gastricdamage; trauma- or stress-induced cell damage; and glycerol-inducedrenal failure. The compounds also act as inhibitors of tumor metastasisand exhibit cytoprotective action.

The cytoprotective activity of a compound may be observed in bothanimals and man by noting the increased resistance of thegastrointestinal mucosa to the noxious effects of strong irritants, forexample, the ulcerogenic effects of aspirin or indomethacin. In additionto lessening the effect of non-steroidal anti-inflammatory drugs on thegastrointestinal tract, animal studies show that cytoprotectivecompounds will prevent gastric lesions induced by oral administration ofstrong acids, strong bases, ethanol, hypertonic saline solutions and thelike.

Two assays can be used to measure cytoprotective ability. These assaysare; (A) an ethanol-induced lesion assay and (B) an indomethacin-inducedulcer assay and are described in EP 140,684.

Dose Ranges

The magnitude of prophylactic or therapeutic dose of a compound ofFormula I will, of course, vary with the nature of the severity of thecondition to be treated and with the particular compound of Formula Iand its route of administration. It will also vary according to the age,weight and response of the individual patient. In general, the dailydose range for anti-asthmatic, anti-allergic or anti-inflammatory useand generally, uses other than cytoprotection, lie within the range offrom about 0.001 mg to about 100 mg per kg body weight of a mammal,preferably 0.01 mg to about 10 mg per kg, and most preferably 0.1 to 1mg per kg, in single or divided doses. On the other hand, it may benecessary to use dosages outside these limits in some cases.

For use where a composition for intravenous administration is employed,a suitable dosage range for anti-asthmatic, anti-inflammatory oranti-allergic use is from about 0.001 mg to about 25 mg (preferably from0.01 mg to about 1 mg) of a compound of Formula I per kg of body weightper day and for cytoprotective use from about 0.1 mg to about 100 mg(preferably from about 1 mg to about 100 mg and more preferably fromabout 1 mg to about 10 mg) of a compound of Formula I per kg of bodyweight per day.

In the case where an oral composition is employed, a suitable dosagerange for anti-asthmatic, anti-inflammatory or anti-allergic use is,e.g. from about 0.01 mg to about 100 mg of a compound of Formula I perkg of body weight per day, preferably from about 0.1 mg to about 10 mgper kg and for cytoprotective use from 0.1 mg to about 100 mg(preferably from about 1 mg to about 100 mg and more preferably fromabout 10 mg to about 100 mg) of a compound of Formula I per kg of bodyweight per day.

For the treatment of diseases of the eye, ophthalmic preparations forocular administration comprising 0.001-1% by weight solutions orsuspensions of the compounds of Formula I in an acceptable ophthalmicformulation may be used.

The exact amount of a compound of the Formula I to be used as acytoprotective agent will depend on, inter alia, whether it is beingadministered to heal damaged cells or to avoid future damage, on thenature of the damaged cells (e.g., gastrointestinal ulcerations vs.nephrotic necrosis), and on the nature of the causative agent. Anexample of the use of a compound of the Formula I in avoiding futuredamage would be co-administration of a compound of the Formula I with anon-steroidal anti-inflammatory drug that might otherwise cause suchdamage (for example, indomethacin). For such use, the compound ofFormula I is administered from 30 minutes prior up to 30 minutes afteradministration of the NSAID. Preferably it is administered prior to orsimultaneously with the NSAID, (for example, in a combination dosageform).

Pharmaceutical Compositions

Any suitable route of administration may be employed for providing amammal, especially a human with an effective dosage of a compound of thepresent invention. For example, oral, rectal, topical, parenteral,ocular, pulmonary, nasal, and the like may be employed. Dosage formsinclude tablets, troches, dispersions, suspensions, solutions, capsules,creams, ointments, aerosols, and the like.

The pharmaceutical compositions of the present invention comprise acompound of Formula I as an active ingredient or a pharmaceuticallyacceptable salt thereof, and may also contain a pharmaceuticallyacceptable carrier and optionally other therapeutic ingredients. Theterm "pharmaceutically acceptable salts" refers to salts prepared frompharmaceutically acceptable non-toxic bases or acids including inorganicbases or acids and organic bases or acids.

The compositions include compositions suitable for oral, rectal,topical, parenteral (including subcutaneous, intramuscular, andintravenous), ocular (ophthalmic), pulmonary (nasal or buccalinhalation), or nasal administration, although the most suitable routein any given case will depend on the nature and severity of theconditions being treated and on the nature of the active ingredient.They may be conveniently presented in unit dosage form and prepared byany of the methods well-known in the art of pharmacy.

For administration by inhalation, the compounds of the present inventionare conveniently delivered in the form of an aerosol spray presentationfrom pressurized packs or nebulisers. The compounds may also bedelivered as powders which may be formulated and the powder compositionmay be inhaled with the aid of an insufflation powder inhaler device.The preferred delivery system for inhalation is a metered doseinhalation (MDI) aerosol, which may be formulated as a suspension orsolution of a compound of Formula I in suitable propellants, such asfluorocarbons or hydrocarbons.

Suitable topical formulations of a compound of Formula I includetransdermal devices, aerosols, creams, ointments, lotions, dustingpowders, and the like.

In practical use, the compounds of Formula I can be combined as theactive ingredient in intimate admixture with a pharmaceutical carrieraccording to conventional pharmaceutical compounding techniques. Thecarrier may take a wide variety of forms depending on the form ofpreparation desired for administration, e.g., oral or parenteral(including intravenous). In preparing the compositions for oral dosageform, any of the usual pharmaceutical media may be employed, such as,for example, water, glycols, oils, alcohols, flavoring agents,preservatives, coloring agents and the like in the case of oral liquidpreparations, such as, for example, suspensions, elixirs and solutions;or carriers such as starches, sugars, microcrystalline cellulose,diluents, granulating agents, lubricants, binders, disintegrating agentsand the like in the case of oral solid preparations such as, forexample, powders, capsules and tablets, with the solid oral preparationsbeing preferred over the liquid preparations. Because of their ease ofadministration, tablets and capsules represent the most advantageousoral dosage unit form in which case solid pharmaceutical carriers areobviously employed. If desired, tablets may be coated by standardaqueous or nonaqueous techniques.

In addition to the common dosage forms set out above, the compounds ofFormula I may also be administered by controlled release means and/ordelivery devices such as those described in U.S. Pat. Nos. 3,845,770;3,916,899; 3,536,809; 3,598,123; 3,630,200 and 4,008,719, thedisclosures of which are hereby incorporated herein by reference.

Pharmaceutical compositions of the present invention suitable for oraladministration may be presented as discrete units such as capsules,cachets or tablets each containing a predetermined amount of the activeingredient, as a powder or granules or as a solution or a suspension inan aqueous liquid, a non-aqueous liquid, an oil-in-water emulsion or awater-in-oil liquid emulsion. Such compositions may be prepared by anyof the methods of pharmacy but all methods include the step of bringinginto association the active ingredient with the carrier whichconstitutes one or more necessary ingredients. In general, thecompositions are prepared by uniformly and intimately admixing theactive ingredient with liquid carriers or finely divided solid carriersor both, and then, if necessary, shaping the product into the desiredpresentation. For example, a tablet may be prepared by compression ormolding, optionally with one or more accessory ingredients. Compressedtablets may be prepared by compressing in a suitable machine, the activeingredient in a free-flowing form such as powder or granules, optionallymixed with a binder, lubricant, inert diluent, surface active ordispersing agent. Molded tablets may be made by molding in a suitablemachine, a mixture of the powdered compound moistened with an inertliquid diluent. Desirably, each tablet contains from about 2.5 mg toabout 500 mg of the active ingredient and each cachet or capsulecontains from about 2.5 to about 500 mg of the active ingredient.

The following are examples of representative pharmaceutical dosage formsfor the compounds of Formula I:

    ______________________________________                                        Injectable Suspension (I.M.)                                                                         mg/ml                                                  Compound of Formula I  10                                                     Methylcellulose        5.0                                                    Tween 80               0.5                                                    Benzyl alcohol         9.0                                                    Benzalkonium chloride  1.0                                                    Water for injection to a total                                                volume of 1 ml                                                                Tablet                 mg/tablet                                              Compound of Formula I  25                                                     Microcrystalline Cellulose                                                                           415                                                    Providone              14.0                                                   Pregelatinized Starch  43.5                                                   Magnesium Stearate     2.5                                                                           500                                                    Capsule                mg/capsule                                             Compound of Formula I  25                                                     Lactose Powder         573.5                                                  Magnesium Stearate     1.5                                                                           600                                                    Aerosol                Per canister                                           Compound of Formula I  24      mg                                             Lecithin, NF Liquid Concentrate                                                                      1.2     mg                                             Trichlorofluoromethane, NF                                                                           4.025   gm                                             Dichlorodifluoromethane, NF                                                                          12.15   gm                                             ______________________________________                                    

Combinations with Other Drugs

In addition to the compounds of Formula I, the pharmaceuticalcompositions of the present invention can also contain other activeingredients, such as cyclooxygenase inhibitors, non-steroidalanti-inflammatory drugs (NSAIDs), peripheral analgesic agents such aszomepirac diflunisal and the like. The weight ration of the compound ofthe Formula I to the second active ingredient may be varied and willdepend upon the effective dose of each ingredient. Generally, aneffective dose of each will be used. Thus, for example, when a compoundof the Formula I is combined with an NSAID the weight ratio of thecompound of the Formula I to the NSAID will generally range from about1000:1 to about 1:1000, preferably about 200:1 to about 1:200.Combinations of a compound of the Formula I and other active ingredientswill generally also be within the aforementioned range, but in eachcase, an effective dose of each active ingredient should be used.

NSAIDs can be characterized into five groups:

(1) the propionic acid derivatives;

(2) the acetic acid derivatives;

(3) the fenamic acid derivatives;

(4) the biphenylcarboxylic acid derivatives; and

(5) the oxicams;

or a pharmaceutically acceptable salt thereof.

The propionic acid derivatives which may be used comprise: alminoprofen,benoxaprofen, bucloxic acid, carprofen, fenbufen, fenoprofen, fluprofen,flurbiprofen, ibuprofen, indoprofen, ketoprofen, miroprofen, naproxen,oxaprozin, pirprofen, prano-profen, suprofen, tiaprofenic acid, andtioxaprofen. Structurally related propionic acid derivatives havingsimilar analgesic and anti-inflammatory properties are also intended tobe included in this group.

Thus, "propionic acid derivatives" as defined herein are non-narcoticanalgesics/non-steroidal anti-inflammatory drugs having a free--CH(CH₃)COOH or --CH₂ CH₂ COOH group (which optionally can be in theform of a pharmaceutically acceptable salt group, e.g., --CH(CH₃)COO⁻Na⁺ or --CH₂ CH₂ COO⁻ Na⁺), typically attached directly or via acarbonyl function to a ring system, preferably to an aromatic ringsystem.

The acetic acid derivatives which may be used comprise: indomethacin,which is a preferred NSAID, acemetacin, alclofenac, clidanac,diclofenac, fenclofenac, fenclozic acid, fentiazac, furofenac, ibufenac,isoxepac, oxpinac, sulindac, tiopinac, tolmetin, zidometacin, andzomepirac. Structually related acetic acid derivatives having similaranalgesic and anti-inflammatory properties are also intended to beencompassed by this group.

Thus, "acetic acid derivatives" as defined herein are non-narcoticanalgesics/non-steroidal anti-inflammatory drugs having a free --CH₂COOH group (which optionally can be in the form of a pharmaceuticallyacceptable salt group, e.g. --CH₂ COO⁻ Na⁺), typically attached directlyto a ring system, preferably to an aromatic or heteroaromatic ringsystem.

The fenamic acid derivatives which may be used comprise: flufenamicacid, meclofenamic acid, mefenamic acid, niflumic acid and tolfenamicacid. Structurally related fenamic acid derivatives having similaranalgesic and anti-inflammatory properties are also intended to beencompassed by this group.

Thus, "fenamic acid derivatives" as defined herein are non-narcoticanalgesics/non-steroidal anti-inflammatory drugs which contain the basicstructure: ##STR4## which can bear a variety of substituents and inwhich the free --COOH group can be in the form of a pharmaceuticallyacceptable salt group, e.g., --COO⁻ Na⁺.

The biphenylcarboxylic acid derivatives which can be used comprise:diflunisal and flufenisal. Structurally related biphenylcarboxylic acidderivatives having similar analgesic and anti-inflammatory propertiesare also intended to be encompassed by this group.

Thus, "biphenylcarboxylic acid derivatives" as defined herein arenon-narcotic analgesics/non-steroidal anti-inflammatory drugs whichcontain the basic structure: ##STR5## which can bear a variety ofsubstituents and in which the free --COOH group can be in the form of apharmaceutically acceptable salt group, e.g., --COO⁻ Na⁺.

The oxicams which can be used in the present invention comprise:isoxicam, piroxicam, sudoxicam and tenoxican. Structurally relatedoxicams having similar analgesic and anti-inflammatory properties arealso intended to be encompassed by this group.

Thus, "oxicams" as defined herein are non-narcoticanalgesics/non-steroidal anti-inflammatory drugs which have the generalformula: ##STR6## wherein R is an aryl or heteroaryl ring system.

The following NSAIDs may also be used: amfenac sodium, aminoprofen,anitrazafen, antrafenine, auranofin, bendazac lysinate, benzydanine,beprozin, broperamole, bufezolac, cinmetacin, ciproquazone, cloximate,dazidamine, deboxamet, delmetacin, detomidine, dexindoprofen, diacerein,di-fisalamine, difenpyramide, emorfazone, enfenamic acid, enolicam,epirizole, etersalate, etodolac, etofenamate, fanetizole mesylate,fenclorac, fendosal, fenflumizole, feprazone, floctafenine, flunixin,flunoxaprofen, fluproquazone, fopirtoline, fosfosal, furcloprofen,glucametacin, guaimesal, ibuproxam, isofezolac, isonixim, isoprofen,isoxicam, lefetamine HCl, leflunomide, lofemizole, lonazolac calcium,lotifazole, loxoprofen, lysin clonixinate, meclofenamate sodium,meseclazone, nabumetone, nictindole, nimesulide, orpanoxin, oxametacin,oxapadol, perisoxal citrate, pimeprofen, pimetacin, piproxen, pirazolac,pirfenidone, proglumetacin maleate, proquazone, pyridoxiprofen,sudoxicam, talmetacin, talnifumate, tenoxicam, thiazolinobutazone,thielavin B, tiaramide HCl, tiflamizole, timegadine, tolpadol, tryptamidand ufenamate.

The following NSAIDs, designated by company code number (see e.g.,Pharmaprojects), may also be used 480156S, AA861, AD1590, AFP802,AFP860, AI77B, AI77B, AP504, AU8001, BPPC, BW540C, CHINOIN 127, CN100,EB382, EL508, F1044, GV3658, ITF182, KCNTEI6090, KME4, LA2851, MR714,MR897, MY309, ONO3144, PR823, PV102, PV108, R830, RS2131, SCR152, SH440,SIR133, SPAS510, SQ27239, ST281, SY6001, TA60, TAI-901(4-benzoyl-1-indancarboxylic acid), TVX2706, U60257, UR2301, andWY41770.

Finally, NSAIDs which may also be used include the salicylates,specifically acetyl salicylic acid and the phenylbutazones, andpharmaceutically acceptable salts thereof.

In addition to indomethacin, other preferred NSAIDs are acetyl salicylicacid, diclofenac, fenbufen, fenoprofen, flurbiprofen, ibuprofen,ketoprofen, naproxen, phenylbutazone, piroxicam, sulindac and tolmetin.Pharmaceutical compositions comprising the Formula I compounds may alsocontain inhibitors of the biosynthesis of the leukotrienes such as aredisclosed in EP 138,481 (Apr. 24, 1985), EP 115,394 (Aug. 8, 1984), EP136,893 (Apr. 10, 1985), and EP 140,709 (May 8, 1985), which are herebyincorporated herein by reference.

The compounds of the Formula I may also be used in combination withleukotriene antagonists such as those disclosed in EP 106,565 (Apr. 25,1984) and EP 104,885 (Apr. 4, 1984) which are hereby incorporated hereinby reference and others known in the art such as those disclosed in EPApplication Nos. 56,172 (Jul. 21, 1982) and 61,800 (Jun. 10, 1982); andin U.K. Patent Specification No. 2,058,785 (Apr. 15, 1981), which arehereby incorporated herein by reference.

Pharmaceutical compositions comprising the Formula I compounds may alsocontain as the second active ingredient, prostaglandin antagonists suchas those disclosed in EP 11,067 (May 28, 1980) or thromboxaneantagonists such as those disclosed in U.S. Pat. No. 4,237,160. They mayalso contain histidine decarboxylase inhibitors such asα-fluoromethylhistidine, described in U.S. Pat. No. 4,325,961. Thecompounds of the Formula I may also be advantageously combined with anH₁ - or H₂ -receptor antagonist, such as for instance acetamazole,aminothiadiazoles disclosed in EP 40,696 (Dec. 2, 1981), benadryl,cimetidine, famotidine, framamine, histadyl, phenergan, ranitidine,terfenadine and like compounds, such as those disclosed in U.S. Pat.Nos. 4,283,408; 4,362,736; and 4,394,508. The pharmaceuticalcompositions may also contain a K⁺ /H⁺ ATPase inhibitor such asomeprazole, disclosed in U.S. Pat. No. 4,255,431, and the like.Compounds of Formula I may also be usefully combined with most cellstabilizing agents, such as1,3-bis(2-carboxychromon-5-yloxy)-2-hydroxypropane and related compoundsdescribed in British Patent Specifications 1,144,905 and 1,144,906.Another useful pharmaceutical composition comprises the Formula Icompounds in combination with serotonin antagonists such asmethysergide, the serotonin antagonists described in Nature, Vol. 316,pages 126-131, 1985, and the like. Each of the references referred to inthis paragraph is hereby incorporated herein by reference.

Other advantageous pharmaceutical compositions comprise the Formula Icompounds in combination with anti-cholinergics such as ipratropiumbromide, bronchodilators such as the beta agonist salbutamol,metaproterenol, terbutaline, fenoterol and the like, and theanti-asthmatic drugs theophylline, choline theophyllinate andenprofylline, the calcium antagonists nifedipine, diltiazem,nitrendipine, verapamil, nimodipine, felodipine, etc. and thecorticosteroids, hydrocortisone, methylprednisolone, betamethasone,dexamethasone, beclomethasone, and the like.

Methods of Synthesis

Compounds of the formula I of the present invention may be preparedaccording to the synthetic routes outlined in the Schemes I to VII andby following the methods described herein.

SCHEME I

The lactone intermediate IX of Scheme I may be prepared, in a multistepsequence, from 3-benzyloxy benzaldehyde (II). The aldehyde II is firstlyconverted to the dibromide product III by treatment with CBr₄ andtriphenylphosphine in an organic solvent such as CH₂ Cl₂. Subsequenttreatment of III with base such as n-butyllithium in an organic solventsuch as THF followed by quenching with CO₂ leads to the acid IV.Conversion of IV to the ester V via the acyl chloride is achieved bytreatment of IV with oxalyl chloride in an organic solvent such astoluene and DMF followed by addition of a 3-aryl-2-propyn-1-ol and abase such as Et₃ N in an organic solvent such as THF. The intramolecularcyclisation of the ester V to provide VI is achieved by heating in anorganic acid such as acetic acid. From this reaction, two side-products(VII and VIII) may also be isolated in varying amounts. Thedebenzylation process is achieved under acidic conditions such as HCl inhot acetic acid leading to the lactone intermediate IX.

SCHEME II

The lactone intermediate IX may also be prepared from a2-bromo-5-benzyloxy benzaldehyde dimethyl acetal X as outlined in SchemeII. The bromo derivative X is converted to the alcohol XI by treatmentwith a base such as n-butyllithium in an organic solvent such as hexanefollowed by the addition of an aryl carboxaldehyde such as benzaldehydein an organic solvent such as THF. The Diels-Alder reaction is achievedby heating the alcohol XI in the presence of maleic anhydride in anorganic solvent such as toluene, providing the anhydride XII. Thereduction of the anhydride XII by treatment with a reducing agent suchas Zn(BH₄)₂ in an organic solvent such as DMF provides the lactone VI.The debenzylation process to provide the lactone IX is described inScheme I.

SCHEME III

An alternate route may also be used to prepare the lactone intermediateIX as outlined in Scheme III. The 2-bromo-5-benzyloxybenzaldehyde XIV isfirstly converted to the thioacetal XV by treatment with1,3-propanedithiol in the presence of a Lewis acid such as BF₃.Et₂ O inan organic solvent such as CH₂ Cl₂. The bromothioacetal XV is convertedto the alcohol XVI under treatment with a base such as n-butyllithium inan organic solvent such as hexane followed by the addition of an arylcarboxaldehyde such as benzaldehyde in an organic solvent such as THF.Heating the alcohol XVI in the presence of maleic anhydride in anorganic solvent such as toluene, provides the Diels-Alder adduct XII.The final conversion of the anhydride XII to the lactone intermediate IXvia the benzylated lactone VI is described above.

SCHEME IV

Another route which may be used to provide the lactone intermediate IXis outlined in Scheme IV. The bromoacetal X is firstly converted to theketoacetal XVII by treatment with a base such as n-butyllithium in anorganic solvent such as hexane in the presence of CuBr.SMe₂ followed bythe addition of an aroyl halide such as benzoyl chloride in an organicsolvent such as THF. The ketoacetal XVII is hydrolysed to theketoaldehyde XVIII by acidic treatment such as HCl in acetone-water. TheDiels-Alder reaction is achieved by heating the ketone XVIII in thepresence of an N-arylmaleimide such as N-phenylmaleimide andtriethylphosphite in an organic solvent such as benzene, providing theimide XIX. The imide XIX is hydrolysed to the dicarboxylic acid XX underbasic conditions such as NaOH in water, then after acidification withacid, such as HCl in water, and treatment with trifluoroaceticanhydride, the anhydride XII is isolated. The final conversion of XII tothe lactone intermediate IX is described in Scheme II.

SCHEME V

The preparation of compounds of Formula I (wherein X³ =--CH₂ O--) isdescribed in Scheme V. Coupling of the phenol lactone IX with theappropriate benzyl halide XXI such as3-[4-(4-methoxy)tetrahydropyranyl]benzyl bromide in an organic solventsuch as DMF using an inorganic base such as K₂ CO₃ provides compounds offormula I (wherein X³ =--CH₂ O--) of the present invention.

SCHEME VI

The synthesis of compounds of Formula I (wherein X³ =--OCH₂ --) isdescribed in Scheme VI. The phenol lactone IX is converted to thetriflate XXII by treatment with trifluoromethanesulfonic anhydride inthe presence of an organic base such as pyridine in a solvent such asCH₂ Cl₂. Subsequent treatment of XXII in a solvent such as DMSO/methanolwith an organic base such as triethylamine, a phosphine such as1,1'-bis(diphenylphosphino)ferrocene, a palladium(II) salt such aspalladium(II)acetate under an atmosphere of carbon monoxide leads to theester XXIII. The hydrolysis of the ester XXIII is achieved using aninorganic base such as lithium hydroxide in water and the resulting acidXXIV is reduced to the alcohol XXV by treatment with a chloroformatesuch as isopropyl chloroformate in the presence of an organic base suchas triethylamine in an organic solvent such as THF, followed by additionof a reducing agent such as sodium borohydride in water. The alcohol XXVis then converted to the halide XXVI by treatment withtriphenylphosphine, imidazole and CBr₄ in an organic solvent such as CH₂Cl₂. Coupling of halide XXVI with the appropriate phenol XXVII such as3-[4-(4-methoxy)tetrahydropyranyl]phenol in an organic solvent such asDMF using an inorganic base such as K₂ CO₃ provides compounds of formulaI (wherein X³ =--OCH₂ --) of the present invention.

SCHEME VII

Scheme VII illustrates the conversion of formula I (wherein R⁵ /R⁶ =H)to formula I (wherein R⁵ /R⁶ =H). Compounds of formula I (R⁵ /R⁶ =H) arealkylated by treatment with an organic base such as lithiumdiisopropylamide in an organic solvent such as THF, followed byquenching with an alkyl halide such as methyl iodide. A secondalkylation may be achieved by using the same conditions. Conversion ofcompounds of formula I (R⁵ /R⁶ =H) to compounds I (wherein R⁵ =OH, R⁶=H) may be achieved by an hydrolysis process using an inorganic basesuch as NaOH in a solvent such as EtOH/H₂ O to provide the carboxylatesalt XXVIII, followed by an oxidation step using an oxidizing agent suchas pyridinium chlorochromate in an organic solvent such as CH₂ Cl₂.

The reaction of compound I (R⁵ =OH, R⁶ =H) with a lower alkyl Grignardor lithium reagent will yield compound I (R⁵ =lower alkyl, R⁶ =H).

SCHEME VIII

Another alternative route which may be used to prepare the lactone IX isoutlined in Scheme VIII. The aryl carboxaldehyde XXIX is converted tothe thioacetal XXX by treatment with thiophenol in the presence of aLewis-Acid such as BF₃.Et₂ O in an organic solvent such as isopropylacetate. The thioacetal XXX is then converted to the lactone XXXII bytreatment with a base such as n-butyl lithium in an organic solvent suchas THF followed by the successive additions of 2-(5H) furanone and thebenzyloxyaryl carboxaldehyde XXXI in an organic solvent such as THF andafter quenching with an acid such as HOAc. The cyclization, dehydrationand debenzylation are achieved simultaneously by heating the lactoneXXXII in the presence of an acid such as trifluoroacetic acid, and usingthioanisole as organic solvent providing the lactone IX. ##STR7##

Representative Compounds

Tables 1 and 2 illustrates compounds of Formulas Ia and Ib, which arerepresentative of the present invention.

                                      TABLE 1                                     __________________________________________________________________________     ##STR8##                            Ia                                       EX. R.sup.1                                                                             R.sup.3                                                                              R.sup.5                                                                           R.sup.8                                                                           X.sup.1                                                                            X.sup.2                                                                            X.sup.3                                    __________________________________________________________________________     1  H     H      H   H   O    C(OMe)                                                                             CH.sub.2 O                                  2  H     H      H   H   O    C(OMe)                                                                             OCH.sub.2                                   3  H     H      H   4-F O    C(OMe)                                                                             CH.sub.2 O                                  4  H     H      H   H   O    C(OH)                                                                              CH.sub.2 O                                  5  H     H      H   H   O    C(OEt)                                                                             CH.sub.2 O                                  6  H     H      H   H   CH.sub.2                                                                           C(OMe)                                                                             CH.sub.2 O                                  7  H     H      H   H   O    N    CH.sub.2 O                                  8  H     H      H   H   O    N(O) CH.sub.2 O                                  9  H     H      OH  H   O    C(OMe)                                                                             CH.sub.2 O                                 10  OH    H      H   H   O    C(OMe)                                                                             CH.sub.2 O                                 11  OH    H      H   H   O    C(OH)                                                                              CH.sub.2 O                                 12  H     H      OH  H   O    C(OH)                                                                              CH.sub.2 O                                 13  OH    H      OH  H   O    C(OH)                                                                              CH.sub.2 O                                 14  H     H      Me  H   O    C(OMe)                                                                             CH.sub.2 O                                 15  OH    H      OH  H   O    C(OMe)                                                                             CH.sub.2 O                                  16*                                                                              Me    Me     H   H   O    C(OH)                                                                              CH.sub.2 O                                  17*                                                                              Me    Me     H   H   O    C(OH)                                                                              CH.sub.2 O                                 18  H     H      H   4-Cl                                                                              O    C(OH)                                                                              CH.sub.2 O                                 19  H     H      H   4-OMe                                                                             O    C(OH)                                                                              CH.sub.2 O                                 20  Me    Me     H   H   O    C(OMe)                                                                             CH.sub.2 O                                 21  H     H      H   H   S    C(OH)                                                                              CH.sub.2 O                                 22  H     H      H   H   S(O) C(OH)                                                                              CH.sub.2 O                                 23  H     H      H   H   S(O).sub.2                                                                         C(OH)                                                                              CH.sub.2 O                                  24**                                                                             OMe   H      H   H   O    C(OH)                                                                              CH.sub.2 O                                  25**                                                                             OMe   H      H   H   O    C(OH)                                                                              CH.sub.2 O                                 26  H     H      H   H   O    C(Me)                                                                              CH.sub.2 O                                 27  H     H      Me  H   O    C(OH)                                                                              CH.sub.2 O                                 28  H     H      H   4-F O    C(OH)                                                                              CH.sub.2 O                                 29  H     H      H   H   O    C(Et)                                                                              CH.sub.2 O                                 30  H     H      H   2-F O    C(OH)                                                                              CH.sub.2 O                                 31  H     H      H   2-Cl                                                                              O    C(OH)                                                                              CH.sub.2 O                                 32  H     H      H   3-OMe                                                                             O    C(OH)                                                                              CH.sub.2 O                                  33**                                                                             OCH(Me).sub.2                                                                       H      H   H   O    C(OH)                                                                              CH.sub.2 O                                  34**                                                                             OCH(Me).sub.2                                                                       H      H   H   O    C(OH)                                                                              CH.sub.2 O                                 35  (R.sup.1 R.sup.3)                                                                   CHCH   H   H   O    C(OH)                                                                              CH.sub.2 O                                 36  (R.sup.1 R.sup.3)                                                                   CH.sub.2 CH.sub.2                                                                    H   H   O    C(OH)                                                                              CH.sub.2 O                                 __________________________________________________________________________     *cis and trans isomers                                                        **axial and equatorial isomers                                           

                  TABLE 2                                                         ______________________________________                                         ##STR9##                      Ib                                             wherein the substituents are:                                                 EX.  R.sup.1  R.sup.2                                                                              R.sup.3                                                                            R.sup.4                                                                            R.sup.5                                                                            R.sup.6                                                                            R.sup.9                                                                            R.sup.10                                                                           X.sup.1                    ______________________________________                                        37   H        H      H    H    H    H    H    4-   O                                                                        OMe                             38   H        H      H    H    Me   Me   H    H    O                          39   H        H      H    H    H    H    1-   H    O                                                                   OMe                                  40   Me       Me     Me   Me   H    H    H    H    S                          41   (R.sup.1 R.sup.2)                                                                      O      H    H    H    H    H    H    O                          ______________________________________                                    

Assays for Determining Biological Activity

Compounds of Formula I can be tested using the following assays todetermine their mammalian leukotriene biosynthesis inhibiting activity.

Human 5-Lipoxygenase Inhibitor Screen Objective of the Assay

The objective of the assay is to select agents which specificallyinhibit the activity of human 5-lipoxygenase using a 100,000× gsupernatant fraction prepared from insect cells infected withrecombinant baculovirus containing the coding sequence for human5-lipoxygenase. Enzyme activity is measured spectrophotometrically fromthe optimal rate of conjugated diene formation (A₂₃₄) measured after theincubation of the enzyme with arachidonic acid in the presence of ATP,calcium ions and phosphatidylcholine.

Description of Procedure

The activity of 5-lipoxygenase is measured using a spectrophotometricassay and recombinant human 5-lipoxygenase as a source of enzyme. The100,000× g fraction from S19 cells infected with the recombinantbaculovirus rvH5LO(8-1) containing the coding region sequence for human5-lipoxygenase is prepared as described below. The enzymatic activity ismeasured, using a spectrophotometric assay from the optimal rate ofconjugated diene formation (A₂₃₄) using the procedure described byRiendeau et al. (Biochem. Pharmacol., 38, 2323-2321, 1989) with minormodifications. The incubation mixture contains 50 mM sodium phosphate pH7.4, 0.2 mM ATP, 0.2 mM CaCl₂, 20 μM arachidonic acid (5 μl from a100-fold concentrated solution in ethanol), 12 μg/mlphosphatidylcholine, an aliquot of the 100,000× g fraction (2-10 μl) andinhibitor (0.5 ml final volume). Inhibitors are added as 500-foldconcentrated solutions in DMSO. Reactions are initiated by the additionof an aliquot of the enzyme preparation and the rate of conjugated dieneformation is followed for 2 minutes at room temperature. The reactionsare performed in semi-micro cuvettes (0.7 ml capacity, 10 mm path lengthand 4 mm internal width) and the absorbance changes are recorded with aHewlett-Packard diode array spectrophotometer (HP 8452A) connected tothe ChemStation using UV/VIS Kinetics Software. Enzymatic activity iscalculated from the optimal rate of the reaction by a linear fit of thevariation of A₂₃₄ during the first twenty seconds using the least squaremethod for the equation A₂₃₄ =V_(o) t+A_(o) where V_(o) is the rate, tis the time, and A_(o) is the absorbance at zero time. The results areexpressed as percentages of inhibition of the reaction rate relative tocontrols (typically between 0.15-0.21 AU/min) containing the DMSOvehicle.

Preparation of Lysates from Infected Cells

S19 cells are grown at 27° C. in 100 ml spinner flasks to a cell densityof 1.5-2×10⁶ cells/ml and infected for 44-48 hours with rvH5LO(8-1). Thecells are then collected by centrifugation (900× g for 10 min, at 20°C.), washed twice with Dulbacco's phosphate-buffered saline (pH 7.4) (25ml/2×10⁸ cells) and resuspended at 1.2×10⁷ cells/ml in a homogenizationbuffer containing 50 mM potassium phosphate (pH 7.9) 2 mM EDTA, 1 mMdithiothreitol, 0.5 mM phenylmethylsulfonyl fluoride and 60 μg/mlsoybean trypsin inhibitor. The cells are then lysed by sonication at 4°C. using a Cole Parmer (4710 Series) Ultrasonic homogeniser (3 to 5bursts of 10 sec. with 30 sec. lags, pulse mode, 70% duty cycle, andoutput setting at 3). The preparations are examined under the microscopeto achieve efficient cell lysis (>90%) with minimal sonication. Thelysate is then centrifuged at 100,000× g for 1 hour (Beckman L5-65, 60Ti rotor) at 4° C. and the resulting supernatant (S-100 fraction)brought to 24 μg/ml PC by the addition of a 250-fold concentratedsolution in ethanol. The S-100 fraction (1-3 mg/ml) is stable forseveral hours at 4° C. and can be stored for several months at -70° C.in 20% ethylene glycol with about 50% recovery of activity.

Rat Peritoneal Polymorphonuclear (PMN) Leukocyte Assay

Rats under ether anesthesia are injected (i.p.) with 8 mL of asuspension of sodium caseinate (6 grams in ca. 50 mL water). After 15-24hr. the rats are sacrificed (CO₂) and the cells from the peritonealcavity are recovered by lavage with 20 mL of buffer (Eagles MEMcontaining 30 mM HEPES adjusted to pH 7.4 with NaOH). The cells arepelleted (350× g, 5 min.), resuspended in buffer with vigorous shaking,filtered through lens paper, recentrifuged and finally suspended inbuffer at a concentration of 10 cells/mL. A 500 mL aliquot of PMNsuspension and test compound are preincubated for 2 minutes at 37° C.,followed by the addition of 10 mM A-23187. The suspension is stirred foran additional 4 minutes then bioassayed for LTB₄ content by adding analiquot to a second 500 mL portion of the PMN at 37° C. The LTB₄produced in the first incubation causes aggregation of the second PMN,which is measured as a change in light transmission. The size of theassay aliquot is chosen to give a submaximal transmission change(usually -70%) for the untreated control. The percentage inhibition ofLTB₄ formation is calculated from the ratio of transmission change inthe sample to the transmission change in the compound-free control.

Human Polymorphonuclear (PMN) Leukocyte LTB₄ Assay

A. Preparation of Human PMN. Human blood is obtained by antecubitalvenepuncture from consenting volunteers who have not taken medicationwithin the previous 7 days. The blood is immediately added to 10% (v/v)trisodium citrate (0.13M) or 5% (v/v) sodium heparin (1000 IU/mL). PMNsare isolated from anticoagulated blood by dextran sedimentation oferythrocytes followed by centrifugation through Ficoll-Hypaque (specificgravity 1.077), as described by Boyum.¹ Contaminating erythrocytes areremoved by lysis following exposure to ammonium chloride (0.16M) in Trisbuffer (pH 7.65), and the PMNs resuspended at 5×10⁵ cells/mL in HEPES(15 mM)-buffered Hanks balanced salt solution containing Ca²⁺ (1.4 mM)and Mg²⁺ (0.7 mM), pH 7.4.

B. Generation and Radioimmunoassay of LTB₄. PMNs (0.5 mL; 2.5×10⁵ cells)are placed in plastic tubes and incubated (37° C., 2 min) with testcompounds at the desired concentration or vehicle (DMSO, finalconcentration 0.2%) as control. The synthesis of LTB₄ is initiated bythe addition of calcium ionophore A23187 (final concentration 10 mM) orvehicle in control samples and allowed to proceed for 5 minutes at 37°C. The reactions are then terminated by the addition of cold methanol(0.25 mL) and samples of the entire PMN reaction mixture removed forradioimmunoassay of LTB₄.

Samples (50 mL) of authentic LTB₄ of known concentration inradioimmunoassay buffer (RIA) buffer (potassium phosphate 1 mM; disodiumEDTA 0.1 mM; Thimerosal 0.025 mM; gelatin 0.1%, pH 7.3) or PMN reactionmixture diluted 1:1 with RIA buffer are added to reaction tubes.Thereafter [³ H]-LTB₄ (10 nCi in 100 mL RIA buffer) and LTB₄ -antiserum(100 mL of a 1:3000 dilution in RIA buffer) are added and the tubesvortexed. Reactants are allowed to equilibrate by incubation overnightat 4° C. To separate antibody-bound from free LTB₄, aliquots (50 mL) ofactivated charcoal (3% activated charcoal in RIA buffer containing 0.25%Dextran T-70) are added, the tubes vortexed, and allowed to stand atroom temperature for 10 minutes prior to centrifugation (1500×g; 10 min;4° C.). The supernatants containing antibody-bound LTB₄ are decantedinto vials and Aquasol 2 (4 mL) added. Radioactivity is quantified byliquid scintillation spectrometry. The specificity of the antiserum andthe sensitivity of the procedure have been described by Rokach et al.²The amount of LTB₄ produced in test and control samples is calculated.Inhibitory dose-response curves are constructed using a four-parameteralgorithm and from these the IC₅₀ values determined.

Human Whole Blood Assay in Vitro for LTB₄ Production A. Blood

Blood (60 ml) is collected from male volunteers directly into 10 mlheparinized vacutainers for assay; one volunteer per assay.

B. Test Compounds

Stock solution: Most concentrated working solution (final) multiplied bythe dilution factor (volume of compound vs blood volume); e.g., 60 μMdose×500 (DMSO 1/500)=30 mM stock solution. To calculate the amount ofcompound needed to make stock solution: mol. wt. of drug×1/1000×stockconcentration; e.g., 618×1/1000×30 mM=18.54 mg for 1 ml vehicle eitherDMSO or methanol.

Working Solutions: Serial dilutions of stock with appropriate vehicle.If methanol is used to dissolve compound, then use methanol/BSA solutionto dilute the stock. Methanol/BSA=1 ml 100% methanol=9 ml BSA 1 mg/mlsaline.

Effective conc. in the assay depends upon the test compound (may be 60uM to 0.1 uM). 1/500 dilution for DMSO vehicle=1 μl for 500 μl blood.1/50 dilution for MeOH/BSA=10 μl for 500 μl blood.

C. A23187

50 mM stock solution: 50 mg A23187 for 1.9 ml DMSO in 50 μl aliquots(stored at -20° C.).

Working Solution: 40 μl of 50 mM stock+760 μl homologous plasma=2.5 mMsolution vehicle=plasma.

Effective conc. in assay should be 25 μM (1/100 dilution).

D. Assay

Add 1 μl (DMSO) of 10 μl (MeOH/BSA) of either test compound or vehicle(use 10 μl hamilton syringe to deliver 1-10 μl) to properly labelled 1.5ml Eppendorf tubes. 500 μl of blood is dispensed into each tube, whichis then vortexed, transfered to a plastic box with lid, washed outsidewith methanol, and incubated 15 min. at 37° C. Meanwhile, centrifuge˜2ml blood in microfuge at 12,000× g for 5 minutes to obtain plasma forthe A23187 solution. At the end of the 15 minutes incubations, add 5 μlof the 2.5 mM A23187 working solution or 5 μl of plasma (blanks) intoeach tube. Vortex well and incubate for 30 minutes at 37° C. At the endof the last incubation, the plasma is obtained by centrifugation asdescribed above, and a 100 μl aliquot is placed into 400 μl of 100%methanol. Meanwhile, transfer the remaining 150 μl of plasma into aclean Eppendorf tube and the store at -70° C. The samples are vortexedand centrifuged as before. The supernatant (methanol extract) is storedat -70° C. until RIA for LTB₄ (20 μl aliquot) as in the above human PMNassay.

SAMPLES

    2 blanks=500 μl blood+1 or 10 μl vehicle+5 μl plasma

    4 controls=500 μl blood+1 or 10 μl vehicle+5 μl A23187

    2 drug blanks=500 μl blood+1 or 10 μl highest+5 μl plasma conc. of drug

    X drugs=500 μl blood+1 or 10 μl drug+5 μl A23187

Asthmatic Rat Assay

Rats are obtained from an inbred line of asthmatic rats. Both female(190-250 g) and male (260-400 g) rats are used.

Egg albumin (EA), grade V, crystallized and lyophilized, is obtainedfrom Sigma Chemical Co., St. Louis. Aluminum hydroxide is obtained fromthe Regis Chemical Company, Chicago. Methysergide bimaleate is suppliedby Sandoz Ltd., Basel.

The challenge and subsequent respiratory recordings are carried out in aclear plastic box with internal dimensions 10×6×4 inches. The top of thebox is removable; in use, it is held firmly in place by four clamps andan airtight seal is maintained by a soft rubber gasket. Through thecenter of each end of the chamber a DeVilbiss nebulizer (No. 40) isinserted via an airtight seal and each end of the box also has anoutlet. A Fleisch No. 0000 pneumotachograph is inserted into one end ofthe box and coupled to a Grass volumetric pressure transducer (PT5-A)which is then connected to a Beckman Type R Dynograph throughappropriate couplers. While aerosolizing the antigen, the outlets areopen and the pneumotachograph is isolated from the chamber. The outletsare closed and the pneumotachograph and the chamber are connected duringthe recording of the respiratory patterns. For challenge, 2 mL of a 3%solution of antigen in saline is placed into each nebulizer and theaerosol is generated with air from a small Potter diaphragm pumpoperating at 10 psi and a flow of 8 liters/minute.

Rats are sensitized by injecting (subcutaneously) 1 mL of a suspensioncontaining 1 mg EA and 200 mg aluminum hydroxide in saline. They areused between days 12 and 24 postsensitization. In order to eliminate theserotonin component of the response, rats are pretreated intravenously 5minutes prior to aerosol challenge with 3.0 mgm/kg of methysergide. Ratsare then exposed to an aerosol of 3% EA in saline for exactly 1 minute,then their respiratory profiles are recorded for a further 30 minutes.The duration of continuous dyspnea is measured from the respiratoryrecordings.

Compounds are generally administered either orally 1-4 hours prior tochallenge or intravenously 2 minutes prior to challenge. They are eitherdissolved in saline or 1% methocel or suspended in 1% methocel. Thevolume injected is 1 mL/kg (intravenously) or 10 mL/kg (orally). Priorto oral treatment rats are starved overnight. Their activity isdetermined in terms of their ability to decrease the duration ofsymptoms of dyspnea in comparison with a group of vehicle-treatedcontrols. Usually, a compound is evaluated at a series of doses and anED₅₀ is determined. This is defined as the dose (mg/kg) which wouldinhibit the duration of symptoms by 50%.

Pulmonary Mechanics in Trained Conscious Squirrel Monkeys

The test procedure involves placing trained squirrel monkeys in chairsin aerosol exposure chambers. For control purposes, pulmonary mechanicsmeasurements of respiratory parameters are recorded for a period ofabout 30 minutes to establish each monkey's normal control values forthat day. For oral administration, compounds are dissolved or suspendedin a 1% methocel solution (methylcellulose, 65 HG, 400 cps) and given ina volume of 1 ml/kg body weight. For aerosol administration ofcompounds, a DeVilbiss ultrasonic nebulizer is utilized. Pretreatmentperiods vary from 5 minutes to 4 hours before the monkeys are challengedwith aerosol doses of Ascaris antigen.

Following challenge, each minute of data is calculated by computer as apercent change from control values for each respiratory parameterincluding airway resistance (R_(L)) and dynamic compliance (C_(dyn)).The results for each test compound are subsequently obtained for aminimum period of 60 minutes post challenge which are then compared topreviously obtained historical baseline control values for that monkey.In addition, the overall values for 60 minutes post-challenge for eachmonkey (historical baseline values and test values) are averagedseparately and are used to calculate the overall percent inhibition ofAscaris antigen response by the test compound. For statistical analysis,paired t-test is used. (References: McFarlane, C. S. et al.,Prostaglandins, 28:173-182, 1984, McFarlane, C. S. et al., AgentsActions 22:63-68, 1987.)

Prevention of Induced Bronchoconstriction in Allergic Sheep

A. Rationale. Certain allergic sheep with known sensitivity to aspecific antigen (Ascaris suum) respond to inhalation challenge withacute and late bronchial responses. The time course of both the acuteand the late bronchial responses approximates the time course observedin asthmatics and the pharmacological modification of both responses issimilar to that found in man. The effects of antigen in these sheep arelargely observed in the large airways and are conveniently monitored aschanges in lung resistance or specific lung resistance.

B. Methods Animal Preparation

Adult sheep with a mean weight of 35 kg (range, 18 to 50 kg) are used.All animals used meet two criteria: a) they have a natural cutaneousreaction to 1:1,000 or 1:10,000 dilutions of Ascaris suum extract (GreerDiagnostics, Lenois, N.C.) and b) they have previously responded toinhalation challenge with Ascaris suum with both an acutebronchoconstriction and a late bronchial obstruction (Abraham, W. M.Delehunt, J. C., Yerger, L. and Merchette, B., Am. Rev. Resp. Dis.,1983, 128, 839-44).

Measurement of Airway Mechanics

The unsedated sheep are restrained in a cart in the prone position withtheir heads immobilized. After topical anesthesia of the nasal passageswith 2% lidocaine solution, a balloon catheter is advanced through onenostril into the lower esophagus. The animals are then intubated with acuffed endotracheal tube through the other nostril using a flexiblefiberoptic bronchoscope as a guide. Pleural pressure is estimated withthe esophageal balloon catheter (filled with one ml of air), which ispositioned such that inspiration produces a negative pressure deflectionwith clearly discernible cardiogenic oscillations. Lateral pressure inthe trachea is measured with a sidehole catheter (inner dimension, 2.5mm) advanced through and positioned distal to the tip of thenasotracheal tube. Transpulmonary pressure, the difference betweentracheal pressure and pleural pressure, is measured with a differentialpressure transducer (DP45; Validyne Corp., Northridge, Calif.). For themeasurement of pulmonary resistance (R_(L)), the maximal end of thenasotrachel tube is connected to a pneumotachograph (Fleisch, DynaSciences, Blue Bell, Pa.). The signals of flow and transpulmonarypressure are recorded on an oscilloscope (Model DR-12; Electronics forMedicine, White Plains, N.Y.) which is linked to a PDP-11 Digitalcomputer (Digital Equipment Corp., Maynard, Mass.) for on-linecalculation of R_(L) from transpulmonary pressure, respiratory volumeobtained by integration and flow. Analysis of 10-15 breaths is used forthe determination of R_(L). Thoracic gas volume (V_(tg)) is measured ina body plethysmograph, to obtain specific pulmonary resistance (SR_(L)=R_(L).V_(tg)).

Aerosol Delivery Systems

Aerosols of Ascaris suum extract (1:20) are generated using a disposablemedicalnebulizer (Raindrop®, Puritan Bennett), which produces an aerosolwith a mass median aerodynamic diameter of 6.2 μM (geometric standarddeviation, 2.1) as determined by an electric size analyzer (Model 3030;Thermal Systems, St. Paul, Minn.). The output from the nebulizer isdirected into a plastic t-piece, one end of which is attached to thenasotracheal tube, the other end of which is conected to the inspiratorypart of a Harvard respirator. The aerosol is delivered at a tidal volumeof 500 ml of a rate of 20 per minute. Thus, each sheep receives anequivalent dose of antigen in both placebo and drug trials.

Experimental Protocol

Prior to antigen challenge baseline measurements of SR_(L) are obtained,infusion of the test compound is started 1 hr prior to challenge, themeasurement of SR_(L) repeated and then the sheep undergoes inhalationchallenge with Ascaris suum antigen. Measurements of SR_(L) are obtainedimmediately after antigen challenge and at 1, 2, 3, 4, 5, 6, 6.5, 7,7.5, and 8 hrs after antigen challenge. Placebo and drug tests areseparated by at least 14 days. In a further study, sheep are given abolus dose of the test compound followed by an infusion of the testcompound for 0.5-1 hr prior to Ascaris challenge and for 8 hrs afterAscaris as described above.

Statistical Analysis

A Kruskal-Wallis one way ANOVA test is used to compare the acuteimmediate responses to antigen and the peak late response in thecontrols and the drug treated animals.

PREPARATION OF BENZYL HALIDES Halide 1:3-[4-(4-Methoxy)tetrahydropyranyl]benzyl bromide ##STR10## Step 1:3-[4-(4-Hydroxy)tetrahydropyranyl]toluene

To a solution of 3-bromotoluene (24.3 mL; Aldrich) in THF (250 mL)stirred at -78° C. was added a solution of n-butyl lithium in hexane(1.75M; 114 mL; Aldrich). After 45 min., the resulting white suspensionwas treated with a solution of tetrahydropyran-4-one (18.5 mL; Aldrich)in THF (125 mL). After 45 min. at -78° C., the mixture was stirred for1.5 h at room temperature. Saturated aqueous NH₄ Cl was then added andthe organic phase separated. The aqueous phase was extracted with EtOAc.The combined organic phases were washed with brine, dried (MgSO₄) andevaporated. Flash chromatography of the residue (silica gel;hexane/EtOAc (1:1)) followed by crystallization in hexane/EtOAc affordedthe title compound as a white solid.

Step 2: 3-[4-(4-Methoxy)tetrahydropyranyl]toluene

To a 0° C. solution of the alcohol (38 g; Step 1) in DMF (300 mL) wereadded NaH (60% in mineral oil; 16 g) and methyl iodide (31 mL). Themixture was stirred under nitrogen at room temperature for 15 hoursbefore water (1 L) was added. The aqueous phase was extracted with EtOAcand the combined organic phases were washed with brine, dried (MgSO₄)and evaporated. Flash chromatography of the residue (silica gel;hexane/EtOAc (4:1) yielded the title ether as a colorless liquid.

Step 3: 3-[4-(4-Methoxy)tetrahydropyranyl]benzyl bromide

A mixture of the toluene (16 g) from Step 2, N-bromosuccinimide (14.6 g)and azoisobutyronitrile (AIBN) (127 mg) in CCl₄ (250 mL) was refluxedfor 1.5 hours. Filtration and evaporation of the filtrate gave thedesired benzyl bromide.

Halide 2: 3-[4-(4-Hydroxy)tetrahydropyranyl]benzyl bromide ##STR11##

Following the procedure described for Halide 1, Step 3, but substituting3-[4-(4-hydroxy)tetrahydropyranyl]toluene (from Halide 1, Step 1) for3-[4-(4-methoxy)tetrahydropyranyl]toluene, the title product wasobtained as a yellow oil.

Halide 3: 3-[4-(4-Ethoxy)tetrahydropyranyl]benzyl bromide ##STR12## Step1: 3-[4-(4-Ethoxy)tetrahydropyranyl]toluene

A solution of 3-[4-(4-hydroxy)tetrahydropyranyl]toluene (Halide 1,Step 1) (368 mg) in DMSO (5 mL) was treated with powdered KOH (490 mg)and ethyl iodide (0.38 mL). After the mixture had been stirred at roomtemperature for 22 hours, ether (25 mL) was added. The organic phase wasthen washed with water (2×25 mL) and brine, dried (MgSO₄), andevaporated. Flash chromatography of the residue (silica gel;hexane/EtOAc, (85:15)) afforded the title product as a colorless liquid.

Step 2: 3-[4-(4-Ethoxy)tetrahydropyranyl]benzyl bromide

Following the procedure described in Halide 1, Step 3, but substitutingthe toluene from Halide 3, Step 1 for3-[4-(4-methoxy)tetrahydropyranyl)toluene, the title benzyl bromide wasobtained as an oil.

Halide 4: 3-(1-Methoxycyclohexyl)benzyl bromide ##STR13##

Following the procedure described in Halide 1, Steps 1-3 butsubstituting cyclohexanone for tetrahydropyran-4-one, the title productwas obtained as a liquid.

Halide 5: 3-(N-Morpholino)benzyl chloride ##STR14## Step 1: Ethyl3-(N-morpholino)benzoate

In a glass pressure vessel containing a magnetic stirrer was placedmorpholine (8.7 g; 100 mmol), ethyl 3-bromobenzoate (20.6 g; 90 mmol),cupric oxide (0.79 g; 10 mmol), potassium carbonate (13.8 g; 100 mmol)and pyridine (20 mL). the vessel was closed and heated under pressure at175° C. for 18 hrs. The mixture was cooled and stirred with water anddiethyl ether. The organic layer was separated, washed with water, 1Nhydrochloric acid, dried (MgSO₄), filtered and concentrated. The residuewas chromatographed on silica gel using 15% ethyl acetate in hexane toobtain the title compound in low yield as an oil.

Step 2: 3-(N-Morpholino)benzyl alcohol

To a solution of ethyl 3-(N-morpholino)benzoate (432 mg; 1.8 mmol) inTHF (15 mL) at 0°-5° C. was added lithium aluminum hydride (209 mg; 5.5mmol) in portions under a nitrogen atmosphere. After stirring for 30min., excess water was added dropwise. Diethyl ether and 1N sodiumhydroxide were then added. The organic layer was seperated, dried(MgSO₄), filtered and concentrated to obtain the title compound as anoil which was used as such in the next reaction.

Step 3: 3-(N-Morpholino)benzyl chloride

To a solution of 3-(N-Morpholino)benzyl alcohol (265 mg; 1.3 mmol) andhexamethyl phosphorus triamide (502 μL; 2.7 mmol) in dichloromethane (10mL) was added at room temperature carbon tetrachloride (280 μL; 2.7mmol). The mixture was stirred for 15 minutes and then concentrated.Diethyl ether was added to the residue and the mixture filtered throughcelite. The filtrate was concentrated and the residue chromatographed onsilica gel using 30% ethyl acetate in hexane to obtain the titlecompound. m.p. 52°-55° C.

Halide 6: 3-[4-(4β-Hydroxy-2,6-dimethyl)tetrahydropyranyl]benzyl bromide##STR15## Step 1: 3-Bromo-O-tetrahydropyranylbenzyl alcohol

To a solution of 3-bromobenzyl alcohol (11.5 g; Aldrich) dissolved inCH₂ Cl₂ (100 mL) at 0° C. and p-toluenesulfonic acid monohydrate (116mg) was added 6.2 mL of DHP. The resulting solution was stirred at r.t.for 3 hr. then was quenched with NH₄ OAc. The aqueous phase wasextracted with CH₂ Cl₂. The combined organic phases were washed withbrine, dried (MgSO₄) and evaporated. Flash chromatography of the residue(silica gel; hexane/EtOAc, 9:1) afforded the title compound as an oil.

Step 2: 2.6-Dimethyltetrahydropyran-4-one

A solution of 2,6-dimethyl-γ-pyrone (17 g) in 300 mL of EtOH 95% washydrogenated for 3 days under 70 psi. After filtration over celite,without extraction, the solvent was evaporated and replaced by CH₂ Cl₂.The solution was then treated with 30 g of celite and 48.5 g ofpyridinium chlorochromate. The suspension was stirred for 3 hr. and thereaction was diluted with 300 mL of Et₂ O and then filtered over a padof celite. The filtrate was evaporated to dryness and the residualsolution was then chromatographed using hexane/ether (1:1) to give thetitle compound.

Step 3:3-[4-(4β-Hydroxy-2,6-dimethyl)tetrahydropyranyl]-O-tetrahydropyranylbenzylalcohol

Following the procedure described in Halide 1, Step 1, but substituting3-bromo-O-tetrahydropyranylbenzyl alcohol from Halide 6, Step 1 for3-bromotoluene and substituting 2,6-dimethyltetrahydropyran-4-one fromHalide 6, Step 2 for tetrahydropyran-4-one, the title compound wasobtained as a mixture of α and β isomers (30:70). Both isomers could beisolated from a flash column (hexane/EtOAc 6:4). The β-hydroxy isomer ismore polar than the α-hydroxy isomer.

Step 4: 3-[4-(4β-Hydroxy-2,6-dimethyl)tetrahydropyranyl]benzyl alcohol

The β-hydroxy-THP derivative (1.0 g) obtained in Halide 6, Step 3, wasdissolved in 10 mL of EtOH and treated with 30 mg of p-toluenesulfonicacid. The reaction was stirred at r.t. for 90 min. The EtOH wasevaporated and the resulting syrup was flash chromatographed to give thetitle compound.

Step 5: 3-[4-(4β-Hydroxy-2,6-dimethyl)tetrahydropyranyl]benzyl bromide

To a solution of alcohol (183 mg) from Halide 6, Step 4, in CH₂ Cl₂ (9mL) was added 269 mg of CBr₄. The reaction was then cooled at -30° C.and 298 mg of DIPHOS was added in portions. After 10 min., the reactionwas quenched with a solution (10 mL) of 10% EtOAc in hexane and withoutevaporation, the solvent was poured onto a silica gel column and elutedwith EtOAc/hexane (3:7). The title compound was isolated and usedimmediately in the next step.

Halide 7: 3-[4-(4α-Hydroxy-2,6-dimethyl)tetrahydropyranyl]benzyl bromide##STR16## Step 1: 3-[4-(4α-Hydroxy-2,6-dimethyl)tetrahydropyranyl]benzylalcohol

Following the procedure described in Halide 6, Step 4, but substitutingα-hydroxy-THP derivative from Halide 6, Step 3, for β-hydroxy-THPderivative, the title product was obtained.

Step 2: 3-[4-(4α-Hydroxy-2,6-dimethyl)tetrahydropyranyl]benzyl bromide

Following the procedure described in Halide 6, Step 5, but substitutingthe α-hydroxy alcohol derivative from Halide 7, Step 1 for the β-hydroxyalcohol derivative, the title compound was obtained.

Halide 8: 3-[4-(4-Hydroxy-2-methoxy)tetrahydropyranyl]benzyl bromide##STR17## Step 1: 3-[4-(4-Hydroxy-2,3-dihydropyranyl)]toluene

Following the procedure described in Halide 1, Step 1, but substituting2,3-dihydro-4H-pyran-4-one (J. Org. Chem., 49 1955 (1984)) fortetrahydropyran-4-one, the title compound was obtained as an oil.

Step 2: 3-[4-(3-Bromo-4-hydroxy-2-methoxy)tetrahydropyranyl]toluene

To a cold (10° C.) solution of the alcohol (1.45 g) from Step 1 in MeOH(15 mL) was added NBS (1.36 g) and the resulting mixture stirred for 40minutes. A phosphate buffer solution (pH 7, 50 mL) was added to thereaction mixture and extracted with CH₂ Cl₂ (3×25 mL). The organiclayers were dried over MgSO₄ and evaporated to dryness. Flashchromatography of the residue (silica gel; hexane/EtOAc, 80:20) affordedthe title product as an oil.

Step 3: 3-[4-(4-Hydroxy-2-methoxy)tetrahydropyranyl]toluene

A mixture of the bromo alcohol (480 mg) from Step 2, tributyltinhydride(0.43 mL) and AIBN (2 mg) in toluene (3 mL) was refluxed under nitrogenfor 2 hours. After evaporation, the resulting residue was dissolved inCH₃ CN (20 mL) and washed with hexane (3×10 mL). The acetonitrile layerwas evaporated to dryness and the resulting residue was purified byflash chromatography (silica gel; hexane/EtOAc, 85:15) to afford thetitle compound as an oil.

Step 4: 3-[4-(4-Hydroxy-2-methoxy)tetrahydropyranyl]benzyl bromide

Following the procedure described for Halide 1, Step 3, but substituting3-[4-(4-hydroxy-2-methoxy)tetrahydropyranyl]toluene from Step 3 for3-[4-(4-methoxy)tetrahydropyranyl]toluene, the title product wasobtained as an oil.

Halide 9: 3-[4-(4-Methyl)tetrahydropyranyl]benzyl bromide ##STR18## Step1: 3-[4-(4-Chloro)tetrahydropyranyl]toluene

A solution of 3-[4-(4-hydroxy)tetrahydropyranyl]toluene (Halide 1,Step 1) (0.57 g in CHCl₃ (10 mL)) was added to a slurry of P₂ Cl₅ (1.92g) and K₂ CO₃ (0.41 g) in CHCl₃ (10 mL) and stirred at 0° C. for 35 min.The reaction mixture was filtered. Evaporation of the filtrate affordedthe title compound as a yellow semi-solid.

Step 2: 3-[4-(4-Methyl)tetrahydropyranyl]toluene

To a 0° C. solution of the chloride (452 mg; Step 1) in CH₂ Cl₂ (7 mL)was added a solution of trimethylaluminum in hexane (2.0M; 2.2 mL;Aldrich). The mixture was stirred at room temperature for 19 hoursbefore saturated NaHCO₃ was added. The aqueous phase was extracted twicewith CH₂ Cl₂ and the combined organic phases were dried (MgSO₄) andevaporated. Flash chromatography of the residue (silica gel;hexane/EtOAc, 9:1) yielded the title compound as a colorless liquid.

Step 3: 3-[4-(4-Methyl)tetrahydropyranyl]benzyl bromide

Following the procedure described in Halide 1 Step 3, but substitutingthe toluene from Halide 8, Step 2, for3-[4-(4-methoxy)tetrahydropyranyl]toluene, the title product wasobtained as an oil.

Halide 10: 3-[4-(4-Ethyl)tetrahydropyranyl]benzyl bromide ##STR19##

Following the procedure described in Halide 9, Steps 2-3, butsubstituting triethylaluminum for trimethylaluminum, the title benzylbromide was obtained as an oil.

Halide 11:3-[4-(4α-Hydroxy-2,2,6,6-tetramethyl)tetrahydrothiopyranyl]benzylchloride ##STR20## Step 1:3-[4-(4α-Hydroxy-2,2,6,6-tetramethyl)tetrahydrothiopyranyl]-O-tetrahydropyranylbenzylalcohol

Following the procedure described in Halide 1 Step 1, but substituting3-bromo-O-tetrahydropyranylbenzyl alcohol (Halide 6, Step 1) for3-bromotoluene and tetrahydro-2,2,6,6-tetramethylthiopyran-4-one (J.Org. Chem. 43, 331 (1978)) for tetrahydropyran-4-one, the title compoundwas obtained.

Step 2:3-[4-(4α-Hydroxy-2,2,6,6-tetramethyl)tetrahydrothiopyranyl]benzylalcohol

A solution of the THP derivative (1.5 g) from Step 1, in 20 mL of EtOHand pyridinium p-toluenesulfonate (39 mg) was heated at 55° C. for 3hours. Evaporation of the solvent followed by a flash column(hexane/EtOAc, 7:3) gave the title compound.

Step 3:3-[4-(4α-Hydroxy-2,2,6,6-tetramethyl)tetrahydrothiopyranyl]benzylchloride

To a solution of the alcohol (500 mg) from Step 2, in CH₂ Cl₂ (20 mL)and CCl₄ (250 μL) was added Ph₃ P (515 mg). The reaction was heatedovernight at 70° C. Then the reaction was diluted with 10% EtOAc inhexane and flash chromatographed directly to give the title compound.

Halide 12: 3-[4-(4-Hydroxy)tetrahydrothiopyranyl]benzyl chloride##STR21## Step 1:3-[4-(4-Hydroxy)tetrahydrothiopyranyl]-O-tetrahydropyranylbenzyl alcohol

Following the procedure described in Halide 1 Step 1, but substituting3-bromo-O-tetrahydropyranylbenzyl alcohol from Halide 6, Step 1, for3-bromotoluene and substituting tetrahydrothiopyran-4-one (Aldrich) fortetrahydropyran-4-one, the title compound was obtained.

Step 2: 3-[4-(4-Hydroxy)tetrahydrothiopyranyl]benzyl alcohol

Following the procedure described in Halide 6, Step 4, but substitutingthe THP derivative from Step 1 for the β-hydroxy-THP derivative, thetitle product was obtained.

Step 3: 3-[4-(4-Hydroxy)tetrahydrothiopyranyl]benzyl chloride

To a solution of the alcohol (572 mg, 2.3 mmol) from Step 2, in CH₂ Cl₂(20 mL) and CCl₄ (273 μL) was added Ph₃ P (681 mg). The reaction washeated overnight at 70° C. Then the reaction was diluted with 10% EtOAcin hexane and flash chromatographed directly to give the title compound.

Halide 13: 3-[3-(8-oxabicyclo[3.2.1]oct-6-en-3α-ol)benzyl]chloride##STR22## Step 1:3-[3-(8-Oxabicyclo[3.2.1]oct-6-en-3α-ol)-O-tetrahydropyranylbenzyl]alcohol

Following the procedure described in Halide 1, Step 1, but substituting3-bromo-O-tetrahydropyranylbenzyl alcohol from Halide 6, Step 1, for3-bromotoluene and substituting 8-oxabicyclo[3.2.1]oct-6-en-3-one (J.Amer. Chem. Soc. 100, 1765 (1978)) for tetrahydropyran-4-one, the titlecompound was obtained.

Step 2: 3-[3-(8-Oxabicyclo[3.2.1]oct-6-en-3α-ol)benzyl]alcohol

Following the procedure described in Halide 11 Step 2, but using the THPderivative from Step 1, the title product was obtained.

Step 3: 3-[3-(8-Oxabicyclo[3.2.1]oct-6-en-3α-ol)benzyl]chloride

To a solution of the alcohol (300 mg, 1.3 mmol) obtained from Step 2, inCH₂ Cl₂ (5 mL) and CCl₄ (144 μL) was added Ph₃ P (407 mg). The reactionwas heated overnight at 70° C. The reaction was diluted with 10% EtOAcin hexane and flash chromatographed directly to give the title compound.

Halide 14: 3-[3-(8-Oxabicyclo[3.2.1]octan-3α-ol]benzyl bromide ##STR23##Step 1: 3-[3-(8-Oxabicyclo[3.2.1]oct-6-en-3α-ol)]toluene

Following the procedure described in Halide 1, Step 1, but substituting8-oxabicyclo[3.2.1]oct-6-en-3-one (J. Amer. Chem. Soc. 100, 1765 (1978))for tetrahydropyran-4-one, the title compound was obtained.

Step 2: 3-[3-(8-Oxabicyclo[3.2.1]octan-3α-ol)]toluene

A mixture of the bicyclic alkene (1.50 g) from Step 1 and 10% Pd/C oncarbon (0.5 g) in EtOAc (150 mL) and MeOH (15 mL) was stirred underhydrogen at r.t. for 18 hours. The reaction mixture was then filteredover celite and evaporation of the filtrate afforded a yellow waxysolid. Trituration in ether followed by filtration and evaporation ofthe filtrate then gave a white solid. Purification by flashchromatography (silica gel; hexane/EtOAc, 3:1) yielded the titletoluene.

Step 3: 3-[3-(8-Oxabicyclo[3.2.1]octan-3α-ol)]benzyl bromide

A mixture of the toluene (0.39 g) from Step 2, NBS (0.33 g) and benzoylperoxide (10 mg) in CCl₄ (10 mL) was refluxed and irradiated withvisible light for 1.5 hours. Filtration and evaporation of the filtrategave the title benzyl bromide.

Halide 15: 3-[4-(4-Hydroxy)tetrahydropyranyl]-4-methoxybenzyl chloride##STR24## Step 1: 3-Bromo-4-methoxybenzyl alcohol

To a solution of 9.8 g (42 mmol) of 3-bromo-4-methoxybenzoic acid in THF(100 mL) was added 1M solution of borane in THF (130 mL) at r.t. undernitrogen. The resulting solution was then heated at 75° C. for 30 min.The reaction mixture was then cooled to r.t. and MeOH (0.5 mL) wasslowly added. The mixture was concentrated and successively treated withMeOH (0.5 mL), evaporated (2×) and finally triturated with Et₂ O andfiltered to yield the title product as a solid, m.p.: 49°-54° C.

Step 2: 3-[4-(4-Hydroxy)tetrahydropyranyl]-4-methoxybenzyl alcohol

To a solution of 9.1 g (42 mmol) of 3-bromo-4-methoxybenzyl alcohol fromStep 1 in THF (250 mL) cooled at -78° C. was added n-BuLi (1.6M, 58 mL)and the resulting solution was stirred for 20 min., thentetrahydropyran-4-one (4.6 g) was added dropwise. The mixture was thenallowed to warm to r.t., diluted with brine and extracted with Et₂ O.The organic phase was dried over anhydrous MgSO₄ and evaporated. Theresulting product was purified by flash chromatography using EtOAc aseluant to give the title product.

Step 3: 3-[4-(4-Hydroxy)tetrahydropyranyl]-4-methoxybenzyl chloride

To a solution of 4.0 g (16.8 mmol) of the corresponding diol from Step 2in THF (80 mL) was added NaH (887 mg) by portion at r.t. The resultingmixture was stirred for 1 h then cooled to 5° C. and TsCl (3.8 g) wasadded. The reaction mixture was then stirred at r.t. and LiCl (3 g) wasadded and stirred for 1 hr. The resulting mixture was then transferredto a solution of 20% citric acid and extracted with Et₂ O. The organiclayer was washed with brine, dried over anhydrous MgSO₄, filtered andconcentrated. Purification by flash chromatography using 50% EtOAc inhexane gave 900 mg (21%) of the title product, m.p.: 96°-99° C.

PREPARATION OF LACTONES Lactone 1:7-Hydroxy-3-hydroxymethyl-4-phenyl-2-naphthoic acid, lactone form##STR25## Method A Step 1: 3-Benzyloxy-β,β-dibromostyrene

To a solution of triphenylphosphine (119.6 g) in methylene chloride (420mL) at 0° C. was added a solution of carbon tetrabromide (75.72 g) inmethylene chloride (90 mL). After completion of the addition, themixture was stirred for 10 min. Then a solution of3-(benzyloxy)benzaldehyde (J.A.C.S., 99, 2571 (1977)) (40 g) inmethylene chloride (150 ml) was added. The mixture was stirred for 16hrs at -5° C. After warming to room temperature, the organic layer waswashed with saturated sodium bicarbonate (2×150 ml) and brine (1×150ml), then dried over magnesium sulfate, filtered and the mixture wasconcentrated. Ether (300 ml) was added, causing the formation of aprecipitate which was filtered. The filtrate was concentrated and theprocess repeated 2 times. Finally, the filtrate was concentrated andchromatographed using 10% ethyl acetate in hexane, affording the titlecompound as a solid.

Step 2: 3-Benzyloxyphenylpropiolic acid

To a solution of the dibromide from Step 1 (15 g) in tetrahydrofuran(150 ml) at -78° C. was added slowly n-BuLi (53.4 ml, 1.6M). Then themixture was left to warm to 0° C. and stirred at that temperature for 1hour. Carbon dioxide was bubbled for 10 min. through the mixture whichwas then diluted with water (150 ml) and 10N NaOH (20 ml). The aqueouslayer was washed with ether (2×100 ml), acidified with 6N HCl, andextracted with ethyl acetate (300 ml). The organic layer was washed withbrine (2×150 ml), dried over magnesium sulfate, filtered and the solventevaporated, affording the title compound as a solid.

Step 3: 3-Phenylpropargyl 3-benzyloxyphenylpropiolate

To a solution of acid (7.5 g) from Step 2 in toluene (123.8 ml) andN,N-dimethylformamide (10 ml) at 0° C. was slowly added oxalyl chloride(2.84 ml). The mixture was stirred for 15 min., then slowly transferredinto a solution of 3-phenyl-2-propyn-1-ol (J.O.C., 41, 4089 (1976))(3.93 g) in tetrahydrofuran (82 ml) and triethylamine (9.94 ml) at 0° C.The mixture was stirred for 20 min. then saturated sodium bicarbonate(80 ml) was added, followed by ether (200 ml). The organic layer waswashed with brine (2×100 ml), dried over magnesium sulfate, filtered andthe solvent evaporated. Purification by chromatograph afforded the titlecompound as a solid.

Step 4: 7-Benzyloxy-3-hydroxymethyl-4-phenyl-2-naphthoic acid, lactoneform

A solution of the ester (6 g) from Step 3 in acetic acid (300 ml) washeated to reflux for 6 hours. Then the acetic acid was evaporated.Chromatography on silica gel, eluting with a mixture of EtOAc/CH₂ Cl₂/hexane (5:15:80), afforded the title product, m.p. 180°-181° C.

Two side-products were isolated from this reaction:3-hydroxymethyl-4-phenyl-5-benzyloxy-2-naphthoic acid, lactone form and3-hydroxymethyl-1-(3-benzyloxyphenyl)-2-naphthoic acid, lactone form.

Step 5: 7-Hydroxy-3-hydroxymethyl-4-phenyl-2-naphthoic acid, lactoneform

A solution of the lactone from Step 4 (2.8 g; 7.6 mmol) in acetic acid(80 ml) and 6N hydrochloric acid (15 mL) was refluxed for 7 hours. Themixture was concentrated and then chromatographed using 10% ethylacetate in toluene to obtain the title compound, m.p. 266°-269° C.

Method B: Step 1: 2-(α-Hydroxybenzyl)-5-benzyloxybenzaldehydedimethylacetal

To a solution of 2-bromo-5-benzyloxy benzaldehyde dimethylacetal (Tet.Lett., 22, 5027 (1981)) (130 g) in THF (2.0 L), cooled to -78° C., wasadded dropwise a solution of n-BuLi (210 ml, 1.91M) in hexane. After 15min., a solution of benzaldehyde (48 mL) in THF (50 ml) was addeddropwise. The cooling bath was removed, then the reaction mixture waswarmed slowly (40 min.) to -10° C. and quenched with a saturated NH₄ Clsolution. The reaction mixture was diluted with Et₂ O (2.0L). Theorganic phase decanted, washed with H₂ O (3×), brine, dried over MgSO₄and the solvents evaporated. The residue was chromatographed on silicagel (hexane/EtOAc 95:5 to 85:15) to give the title product as a foam.

Step 2: 7-Benzyloxy-4-phenylnaphthalene-2,3-dicarboxylic anhydride

To a solution of the alcohol (112 g) from Step 1 in toluene (1.1L) wasadded maleic anhydride (150 g). The reaction mixture was heated toreflux for 24 hours. After cooling to room temperature, the toluene wasevaporated. The residue was triturated in EtOAc at 0° C., filtered andwashed with Et₂ O to afford the title product as a white solid.

Step 3: 7-Benzyloxy-3-hydroxymethyl-4-phenyl-2-naphthoic acid, lactoneform

To a solution of the anhydride (2 g) from Step 2 in DMF (40 mL) wasadded a solution of Zn(BH₄)₂ (30 ml of 0.08M in ether) (J.A.C.S., 6074,1960). The resulting reaction mixture was heated at 50° C. for 18 hours.After cooling to room temperature, an aqueous solution of 1N HCl wasadded and the reaction mixture was diluted with ethyl acetate (200 mL),washed with H₂ O (2×), brine, dried over MgSO₄, and the solventevaporated. The reside was purified by chromatography on silica gelusing hexane/ethyl acetate 9:1 to first give the title product as themajor component, followed by a minor product corresponding to7-benzyloxy-2-hydroxymethyl-4-phenyl-3-naphthoic acid, lactone form.

Use of the title product is described in Method A, Step 5.

Method C Step 1: 2-Bromo-5-benzyloxybenzaldehyde propane dithioacetal

To a solution of 2-bromo-5-benzyloxy benzaldehyde (Tet. Lett., 22, 5027(1981)) (51.8 g) in CH₂ Cl₂ (400 mL) was added 1,3-propanedithiol (17.5mL), then BF₃ -Et₂ O (3 mL). The reaction mixture was stirred at roomtemperature for 16 hours then quenched with a saturated solution of NH₄Cl. The organic phase was extracted and washed with a saturated solutionof sodium bicarbonate, H₂ O, brine, dried over MgSO₄ and evaporated. Thesolid residue was recrystallized from hexane/EtOAc to afford the titlecompound.

Step 2: 7-Benzyloxy-4-phenylnaphthalene-2,3-dicarboxylic anhydride

Following the procedures described in Method B, Steps 1 and 2, butsubstituting the thioacetal from Method C, Step 1 for2-bromo-5-benzyloxy benzaldehyde dimethylacetal, the title compound wasobtained as a foam.

Use of the title product is described in Method B, Step 3 and Method A,Step 5.

Method D Step 1: 2-Benzoyl-5-benzyloxybenzaldehyde dimethylacetal

To a solution of 2-bromo-5-benzyloxy benzaldehyde dimethyl acetal (Tet.Lett., 22, 5027 (1981)) (52.2 g) in THF (600 mL), cooled to -78° C., wasadded dropwise a solution of n-BuLi (78 ml, 2.1M) in hexane. After 15min. CuBr.SMe₂ (32 g) was added in 3 portions. The reaction mixture wasstirred at -78° C. until CuBr.SMe₂ was dissolved (approx. 1 hr.), thenbenzoyl chloride (20 mL) was added dropwise. The cooling bath wasremoved and the reaction mixture was stirred at room temperature overnight and was quenched with a saturated NH₄ Cl solution. The organicphase was diluted with Et₂ O, washed with H₂ O (3×), brine, dried(MgSO₄) and evaporated to afford the title compound which was used assuch for the next step.

Step 2: 2-Benzoyl-5-benzyloxybenzaldehyde

A solution of crude ketone from Step 1 in acetone (250 mL) and HCl 10%(25 mL) was stirred for 6 hours, diluted with Et₂ O, washed with asaturated NH₄ Cl solution, H₂ O (3×), brine and dried (MgSO₄). Afterevaporation of the solvent, the residue was saturated with hexane andfiltered to afford the title compound as pale yellow solid.

Step 3: 7-Benzyloxy-4-phenylnaphthalene-2,3-dicarboxylic N-phenylimide

A solution of the keto aldehyde from Step 2 (27.9 g), N-phenyl maleimide(23 g) and triethyl phosphite (24 mL) in benzene (500 mL) was heated atreflux for 3 hours then stirred at room temperature overnight. Thereaction mixture was filtered and the solid washed with Et₂ O to givethe title compound as a pale yellow solid.

Step 4: 7-Benzyloxy-4-phenylnaphthalene-2,3-dicarboxylic acid

A solution of the imide from Step 3 (5.3 g) in triglyme (30 mL) and NaOH(10N, 20 mL) was stirred at 120° C. for 48 hours. The reaction mixturewas cooled, extracted with H₂ O (2×), the water phase acidified to pH 3with conc. HCl, and filtered. The solid residue was dissolved in CHCl₃and washed with H₂ O, brine, dried (MgSO₄) and evaporated to afford thetitle compound which was used as such for the next step.

Step 5: 7-Benzyloxy-4-phenylnaphthalene-2,3-carboxylic anhydride

To a solution of the crude acid from Step 4 in THF (20 mL) at 0° C. wasadded trifluoroacetic anhydride (TFAA) (5 mL) dropwise. The reactionmixture was stirred at 0° C. for 1 hour then at room temperatureovernight. After evaporation of the solution, the residue was trituratedwith Et₂ O and filtered to afford the title compound as a white solid.

Use of the title product is described in Method B, Step 3 and Method A,Step 5.

Method E Step 1: Benzaldehyde phenyl dithioacetal

To a solution of benzaldehyde (31.8 g) and thiophenol (69.2 g) inisopropyl acetate (300 mL), cooled in an ice-water bath, there wasslowly added BF₃.Et₂ O (42.6 g). The resulting mixture was stirred inthe cold for an additional hour. There was slowly added 10% aqueous K₂CO₃ (200 mL) and the phases were separated. The aqueous phase wasextracted with EtOAc and the combined organic layers were washed with10% aq. K₂ CO₃, then with H₂ O (3×), dried and evaporated down to an oilwhich solidified. This solid was stirred in pentane (250 mL) at r.t. for5 hrs and filtered to afford the desired dithioacetal.

Step 2:3-[α,α-bis(Phenylthio)benzyl]-2-(3-benzyloxy-α-hydroxybenzyl)butyrolactone

To a solution of the dithioacetal from Step 1 (23.5 g) in THF (250 mL),at -70° C. there was slowly added 2.1M n-BuLi in hexanes (37 mL). Theresulting yellow suspension was stirred for a further 20 min at -70° C.,then there was added dropwise 2-(5H)furanone (Omega Inc., 7.64 g) and,30 min later, a solution of 3-benzyloxybenzaldehyde (Aldrich, 16.5 g) inTHF (75 mL). The mixture was stirred a further hour at -70° C., thenthere was slowly added glacial HOAc (9.0 g). The mixture was allowed towarm up to r.t., diluted with Et₂ O (300 mL), washed with brine (4×),dried and evaporated. The residue was used as such in the next step.

Step 3: 7-Hydroxy-3-hydroxymethyl-4-phenyl-2-naphthoic acid, lactoneform

The crude product from Step 2 was dissolved in thioanisole (75 mL),there was added TFA (190 mL) and the mixture was heated to 60° C. for 1hr. After cooling, the TFA was evaporated, the residue was diluted withEt₂ O (200 mL) and after 20 min, the insoluble solid was filtered toafford the desired title compound.

Lactone 2: 7-Hydroxy-3-hydroxymethyl-4-(4-fluorophenyl)-2-naphthoicacid, lactone form ##STR26##

Following the procedures described in Lactone 1, Method A, Steps 3-5,but substituting 3-(4-fluorophenyl)-2-propyn-1-ol for3-phenyl-2-propyn-1-ol, the title product was obtained as a solid.

Lactone 3: 7-Hydroxy-3-hydroxymethyl-4-(4-chlorophenyl)-2-naphthoicacid, lactone form

Following the procedure described in Lactone 1, Method B, Steps 1-3,followed by Method A, Step 5, but substituting 4-chlorobenzaldehyde forbenzaldehyde, the title compound was obtained as a solid.

Lactone 4: 7-Hydroxy-3-hydroxymethyl-4-(4-methoxyphenyl)-2-naphthoicacid, lactone form

Following the procedure described in Lactone 1, Method B, Steps 1-3, andfollowed by Method A, Step 5, but substituting 4-methoxybenzaldehyde forbenzaldehyde, the title compound was obtained as a solid.

Lactone 5: 7-Hydroxy-3-hydroxymethyl-4-(2-fluorophenyl)-2-naphthoicacid, lactone form

Following the procedure described in Lactone 1, Method B, Steps 1-3, andfollowed by Method A, Step 5, but substituting 2-fluorobenzaldehyde forbenzaldehyde, the title product was obtained as a white solid.

Lactone 6: 7-Hydroxy-3-hydroxymethyl-4-(2-chlorophenyl)-2-naphthoicacid, lactone form

Following the procedure described in Lactone 1, Method B, Steps 1-3, andfollowed by Method A, Step 5, but substituting 2-chlorobenzaldehyde forbenzaldehyde, the title product was obtained as a white solid.

Lactone 7: 7-Hydroxy-3-hydroxymethyl-4-(3-methoxyphenyl)-2-naphthoicacid, lactone form

Following the procedure described in Lactone 1, Method E, butsubstituting m-anisaldehyde for benzaldehyde, the title compound wasobtained as a white solid.

EXAMPLES

The invention is further defined by reference to the following examples,which are intended to be illustrative and not limiting. All temperaturesare in degrees Celsius.

EXAMPLE 13-Hydroxymethyl-4-phenyl-7-{3-[4-(4-methoxy)tetrahydropyranyl]benzyloxy}-2-naphthoicacid, lactone form

A mixture of 3-[4-(4-methoxy)tetrahydropyranyl]benzyl bromide, (Halide1), (1.04 g), 7-hydroxy-3-hydroxymethyl-4-phenyl-2-naphthoic acidlactone form (Lactone 1) (0.60 g), and potassium carbonate (0.78 g) inDMF (15 mL) was stirred at room temperature. After 17 hours, water wasadded and the aqueous phase was extracted with EtOAc. The combinedorganic phases were washed with 1N NaOH, water and brine before beingdried (MgSO₄) and evaporated. The resulting solid was crystallized inEtOAc to afford the title compound as a pale yellow solid, m.p.191°-192° C.

EXAMPLE 23-Hydroxymethyl-4-phenyl-7-{3-[4-(4-methoxy)tetrahydropyranyl]phenoxymethyl}-2-naphthoicacid, lactone form Step 1:3-Hydroxymethyl-4-phenyl-7-trifluoromethanesulfonyloxy-2-naphthoic acid,lactone form

To a solution of Lactone 1 (141 mg) in CH₂ Cl₂ (25 mL) and pyridine (400μl) at -78° C. was added trifluoromethanesulfonic anhydride (150 μL)dropwise. The reaction mixture was stirred at room temperature for 30min. diluted with Et₂ O, quenched with a saturated NH₄ Cl solution,washed successively with HCl (10%, 2×), H₂ O, brine and dried (MgSO₄).Purification by flash chromatography (hexane/EtOAc, 95% to 85%) gave thetitle compound.

Step 2: 7-Carbomethoxy-3-hydroxymethyl-4-phenyl-2-naphthoic acid,lactone form

To a solution of the triflate ester from Step 1 (160 mg) in DMSO (5 mL)was added. MeOH (3 mL, Et₃ N (110 μL),1,1-bis(diphenylphosphino)ferrocene (50 mg) and Pd(OAc)₂ (10 mg). Thereaction mixture was saturated with carbon monoxide (bubbling for 10min) then heated at 75° C. under a CO atmosphere for 15 min. Thereaction was cooled, diluted with Et₂ O, washed with saturated NH₄ Clsolution, H₂ O, brine and dried (MgSO₄). Evaporation and purification ofthe residue by flash chromatography (hexane/EtOAc/CHCl₃ 75:15:10)afforded the title compound as a pale yellow solid.

Step 3: 7-Carboxy-3-hydroxymethyl-4-phenyl-2-naphthoic acid, lactoneform

To a solution of the lactone from Step 2 (110 mg) in THF/H₂ O (4:1, 10mL) was added LiOH.H₂ O (50 mg). After 30 min., the reaction mixture wasacidified to pH 2-3, and the water phase saturated with NaCl. Theorganic phase was decanted, dried (MgSO₄) and evaporated. The residuewas purified by flash chromatography (CHCl₃ /MeOH, 85:15) to afford thetitle compound.

Step 4: 3,7-Dihydroxymethyl-4-phenyl-2-naphthoic acid, lactone form

To a solution of the acid from Step 3 (94 mg) in THF (10 mL) at -70° C.was added Et₃ N (65 μL), then isopropyl chloroformate (48 μL). After 20min., NaBH₄ (25 mg) in H₂ O (2 mL) was added and the reaction mixturewas stirred at room temperature for 30 min. The reaction was dilutedwith EtOAc and saturated NH₄ Cl solution, washed with H₂ O, brine anddried (MgSO₄). After evaporation, the residue was purified by flashchromatography (CHCl₃ /MeOH, 99:1 to 97:3) to give the title compound.

Step 5: 7-Bromomethyl-3-hydroxymethyl-4-phenyl-2-naphthoic acid, lactoneform

To a solution of the alcohol from Step 4 (76 mg) in CH₂ Cl₂ (10 mL) at0° C. was added Ph₃ P (76 mg), imidazole (20 mg) and CBr₄ (90 mg). Thereaction mixture was stirred 30 min. at 0° C. then diluted with H₂ O,brine and dried (MgSO₄). After evaporation, the residue was purified byflash chromatography (hexane/EtOAc, 85:15) to give the title compound.

Step 6:3-Hydroxymethyl-4-phenyl-7-{3-[4-(4-methoxy)tetrahydropyranyl]phenoxymethyl}-2-naphthoicacid, lactone form

Following the procedure described in Example 1 but substituting3-[4-(4-methoxy)tetrahydropyranyl]phenol (EP-A-351,194) for7-hydroxy-3-hydroxymethyl-4-phenyl-2-naphthoic acid, lactone form, andsubstituting 7-bromomethyl-3-hydroxymethyl-4-phenyl-2-naphthoic for3-[4-(4-methoxy)tetrahydropyranyl]benzyl bromide, the title product wasobtained as a cream colored solid, m.p. 165°-166° C.

EXAMPLE 33-Hydroxymethyl-4-(4-fluorophenyl)-7-{3-[4-(4-methoxy)tetrahydropyranyl]benzyloxy}-2-naphthoicacid, lactone form

Following the procedure described in Example 1 but substituting7-hydroxy-3-hydroxymethyl-4-(4-fluorophenyl)-2-naphthoic acid, lactoneform, (Lactone 2), for 7-hydroxy-3-hydroxymethyl-4-phenyl-2-naphthoicacid, lactone form, the title compound was obtained as a white solid,m.p. 140°-141° C.

EXAMPLE 43-Hydroxymethyl-4-phenyl-7-{3-[4-(4-hydroxy)tetrahydropyranyl]benzyloxy}-2-naphthoicacid, lactone form

Following the procedure described in Example 1 but substituting3-[4-(4-hydroxy)tetrahydropyranyl]benzyl bromide (Halide 2) for3-[4-(4-methoxy)tetrahydropyranyl]benzyl bromide, the title product wasobtained as a white solid, m.p. 191°-192° C.

EXAMPLE 53-Hydroxymethyl-4-phenyl-7-{3-[4-(4-ethoxy)tetrahydropyranyl]benzyloxy}-2-naphthoicacid, lactone form

Following the procedure described in Example 1 but substituting3-[4-(4-ethoxy)tetrahydropyranyl]benzyl bromide (Halide 3) for3-[4-(4-methoxy) tetrahydropyranyl]benzyl bromide, the title compoundwas obtained as a white solid, m.p. 153°-155° C.

EXAMPLE 63-Hydroxymethyl-4-phenyl-7-{3-(1-methoxycyclohexyl)benzyloxy}-2-naphthoicacid, lactone form

Following the procedure described in Example 1 but substituting3-(1-methoxycyclohexyl)benzyl bromide (Halide 4) for3-[4-(4-methoxy)tetrahydropyranyl]benzyl bromide, the title compound wasobtained as a white solid, m.p. 174°-176° C.

EXAMPLE 73-Hydroxymethyl-4-phenyl-7-{3-(N-morpholino)benzyloxy}-2-naphthoic acid,lactone form

Following the procedure described in Example 1 but substituting3-(N-morpholino)benzyl chloride (Halide 5) for3-[4-(4-methoxy)tetrahydropyranyl]benzyl bromide, the title product wasobtained as a white solid, m.p. 194°-196° C.

EXAMPLE 83-Hydroxymethyl-4-phenyl-7-{3-(N-oxomorpholino)benzyloxy}-2-naphthoicacid, lactone form

To a solution of3-hydroxymethyl-4-phenyl-7-[3-(N-morpholino)benzyloxy]-2-naphthoic acid,lactone form (from Example 7) (40 mg; 0.08 mmol) in dichloromethane (5mL) was added 85% meta-chloroperbenzoic acid (28 mg; 0.11 mmol). Themixture was stirred for one hour at room temperature and then excesscalcium hydroxide added. After stirring for 15 minutes the mixture wasfiltered through celite and the filtrate concentrated. The residue waschromatographed using 10% methanol in dichloromethane to obtain thetitle compound, m.p. 199°-200° C.

EXAMPLE 93-Formyl-4-phenyl-7-{3-[4-(4-methoxy)tetrahydropyranyl]benzyloxy}-2-naphthoicacid, lactone form Step 1:3-Hydroxymethyl-4-phenyl-7-{3-[4-(4-methoxy)tetrahydropyranyl]benzyloxy}-2-naphthoicacid, sodium salt

A suspension of the lactone from Example 1, Step 1 (0.50 g) in absoluteethanol (15 mL) was treated with 1N aqueous NaOH (1.2 mL) and refluxedfor 21 hours. The resulting yellow solution was evaporated to drynessand gave the title salt as a yellow solid.

Step 2:3-Formyl-4-phenyl-7-{3-[4-(4-methoxy)tetrahydropyranyl]benzyloxy}-2-naphthoicacid, lactone form

A suspension of3-hydroxymethyl-4-phenyl-7-{3-[4-(4-methoxy)tetrahydropyranyl]benzyloxy}-2-naphthoicacid sodium salt (9 mg) from Example 1 in CH₂ Cl₂ (0.5 mL) was treatedwith pyridinium chlorochromate (5 mg) at room temperature for 40minutes. The mixture was then eluted through a short column of silicagel with 5% methanol in chloroform. Preparative thin layerchromatography of the residue gave the title compound as a colorlessgum.

¹ H NMR (250 MHz, CDCl₃): δ2.00 (m, 4H), 2.99 (s, 3H), 3.85 (m, 4H),5.25 (s, 2H), 6.63 (s, 1H), 7.25-7.55 (m, 12H), 7.69 (d, 1H), and 8.33(s, 1H).

EXAMPLE 113-Hydroxymethyl-4-phenyl-7-[3-[4-(2,4-dihydroxy)tetrahydropyranyl]benzyloxy]-2-naphthoicacid, lactone form Step 1:3-Hydroxymethyl-4-phenyl-7-[3-[4-(4-hydroxy-2-methoxy)tetrahydropyranyl]benzyloxy]-2-naphthoicacid, lactone form

Following the procedure described in Example 1 but substituting3-[4-(4-hydroxy-2-methoxy)tetrahydropyranyl]benzyl bromide (Halide 8)for 3-[4-(4-methoxy)tetrahydropyranyl]benzyl bromide, the title compoundwas obtained as a yellow gum.

Step 2:3-Hydroxymethyl-4-phenyl-7-[3-[4-(2,4-dihydroxy)tetrahydropyranyl]benzyloxy]-2-naphthoicacid, lactone form

To a solution of the methoxy alcohol (85 mg) from Step 1 in THF (1.5 mL)was added 10% aqueous HCl (1 mL) and the resulting solution was stirredat r.t. for 3 hr. The reaction mixture was basified with a solution ofNaHCO₃ and extracted with EtOAc. The organic layer was washed withbrine, dried over MgSO₄, and evaporated to dryness. The residue waspurified by preparative TLC (silica gel; CHCl₃ /EtOAc, 40:60) to affordthe title product as a white solid.

¹ H NMR (250 MHz, CDCl₃): δ1.83 (m, 1H), 2.05 (m,2H), 2.31 (dt, 1H),3.81 (m, 1H), 3.82 (s, 1H), 4.37 (d, 1H), 4.43 (dt, 1H), 5.22 (s, 2H),5.24 (s, 2H), 5.41 (m, 1H), 7.29-7.59 (m, 10H), 7.67 (s, 1H), 7.73 (d,1H) and 8.36 (s, 1H).

EXAMPLE 123-Formyl-4-phenyl-7-[3-[4-(4-hydroxy)tetrahydropyranyl[benzyloxy]-2-naphthoicacid, lactone form

Following the procedure described in Example 9, Steps 1-2, butsubstituting the lactone from Example 4 for the lactone from Example 1,the title compound was obtained as a white solid, m.p. 214°-218° C.

EXAMPLE 163-Hydroxymethyl-4-phenyl-7-[3-[4-(4α-hydroxy-2,6-dimethyl)tetrahydropyranyl]benzyloxy]-2-naphthoicacid, lactone form

Following the procedure described in Example 1 but substituting3-[4-(4α-hydroxy-2,6-dimethyl)tetrahydropyranyl]benzyl bromide (Halide7) for 3-[4-(4-methoxy)tetrahydropyranyl]benzyl bromide (Halide 1) andsubstituting Cs₂ CO₃ for K₂ CO₃, the title compound was obtained as awhite solid.

¹ H NMR (250 MHz, CDCl₃): δ1.2 (d, 6H); 1.5-1.7 (m, 4H); 2.4 (broad s,1H); 4.0 (m, 2H); 5.2-5.3 (2s, 4H); 7.2-7.6 (m, 11H); 7.75 (d, 1H); 8.4(s, 1H).

EXAMPLE 173-Hydroxymethyl-4-phenyl-7-[3-[4-(4β-hydroxy-2,6-dimethyl)tetrahydropyranyl]benzyloxy]-2-naphthoicacid lactone form

Following the procedure described in Example 1 but substituting3-[4-(4β-hydroxy-2,6-dimethyl)tetrahydropyranyl]benzyl bromide (Halide6) for 3-[4-(4-methoxy)tetrahydropyranyl]benzyl bromide (Halide 1) andsubstituting Cs₂ CO₃ for K₂ CO₃, the title compound was obtained as awhite solid.

¹ H NMR (250 MHz, CDCl₃): δ1.2 (d, 6H); 1.65 (t, 2H); 1.9 (broad s, 1H);2.4 (d, 2H); 3.4 (m, 2H); 5.25 (s, 4H); 7.2-7.6 (m, 11H); 7.75 (d, 1H);8.4 (s, 1H).

EXAMPLE 183-Hydroxymethyl-4-(4-chlorophenyl)-7-[3-[4-(4-hydroxy)tetrahydropyranyl]benzyloxy]-2-naphthoicacid, lactone form

A mixture of Lactone 3 (450 mg, 1.45 mmol), Halide 2 (434 mg, 1.6 mmol)and Cs₂ CO₃ (520 mg, 1.6 mmol) in DMF (10 mL) was stirred at r.t. fortwo hr. The mixture was diluted with H₂ O and extracted twice withEtOAc. The extracts were washed twice with brine, dried, and evaporated.The residue was chromatographed on silica gel, eluting with a 60:40mixture of hexane and EtOAc, to afford the title compound. This wasstirred at r.t. in a small volume of Et₂ O for 1 hr and filtered toafford the purified desired product; m.p. 125°-127° C.

EXAMPLE 193-Hydroxymethyl-4-(4-methoxyphenyl)-7-[3-[4-hydroxy)tetrahydropyranyl]benzyloxy]-2-naphthoicacid, lactone form

Following the procedure described in Example 18, but substituting7-hydroxy-3-hydroxy-methyl-4-(4-methoxyphenyl)-2-naphthoic acid, lactoneform (Lactone 4) for7-hydroxy-3-hydroxymethyl-4-(4-chlorophenyl)-2-naphthoic acid, lactoneform (Lactone 3), the title compound was obtained as a solid; m.p.220°-225° C.

EXAMPLE 203-Hydroxymethyl-4-phenyl-7-[3-[4-(4α-methoxy-2,6-dimethyl)tetrahydropyranyl]benzyloxy]-2-naphthoicacid, lactone form

A mixture of3-hydroxymethyl-4-phenyl-7-[3-[4-(4α-hydroxy-2,6-dimethyl)tetrahydropyranyl]benzyloxy]-2-naphthoicacid lactone form (from Example 17) (50 mg) in DMF (1 mL) was stirred atr.t. with excess of NaH and MeI. A solution of NH₄ Cl was added and thereaction mixture was extracted with EtOAc and the combined organic phasewas dried and evaporated. Flash column of the residue with 30% EtOAc inhexane afforded the title compound as a solid; m.p. 195° C.

EXAMPLE 213-Hydroxymethyl-4-phenyl-7-[3-[4-(4-hydroxy)tetrahydrothiopyranyl]benzyloxy]-2-naphthoicacid, lactone form

Following the procedure described in Example 1, but substituting3-[4-(hydroxy)tetrahydrothiopyranyl]benzyl chloride (Halide 12) for3-[4-(4-methoxy)tetrahydropyranyl]benzyl bromide (Halide 1) andsubstituting Cs₂ CO₃ for K₂ CO₃, the title compound was obtained as awhite solid; m.p. 203°-205° C.

EXAMPLE 223-Hydroxymethyl-4-phenyl-7-[3-[4-(4-hydroxy-S-oxo)tetrahydrothiopyranyl]benzyloxy]-2-naphthoicacid, lactone form

To a solution at -78° C. of3-hydroxymethyl-4-phenyl-7-[3-[4-(4-hydroxy)tetrahydrothiopyranyl]benzyloxy-2-naphthoicacid, lactone form (from Example 21) (50 mg; 0.1 mmol) in CH₂ Cl₂ (1 mL)and THF (1 mL) was added 85% meta-chloroperbenzoic acid (21 mg; 0.12mmol). The mixture was stirred for one hr at -78° C. and then filteredthrough celite and the filtrate concentrated. The residue waschromatographed using 5% MeOH in CHCl₃ to obtain the title compound as afoam.

¹ H NMR (250 MHz, CDCl₃): δ1.8 (d, 2H); 2.7-3.4 (m, 7H); 5.2-5.3 (2s,4H); 7.2-7.8 (m, 12H); 8.3 (s, 1H).

EXAMPLE 233-Hydroxymethyl-4-phenyl-7-[3-[4-(4-hydroxy-S,S-dioxo)tetrahydrothiopyranyl]benzyloxy]-2-naphthoicacid, lactone form

Using 3.0 eq. of meta-chloroperbenzoic acid, the procedure described inExample 22 was followed. Aqueous work-up was done using EtOAc/NH₄ OAcextraction (3×). The combined organic layer was dried and evaporated togive, after flash chromatography, the title compound as a solid; m.p.247°-249° C.

EXAMPLES 24 AND 253-Hydroxymethyl-4-phenyl-7-[3-[4-(4-hydroxy-2α-methoxy-tetrahydropyranyl]benzyloxy]-2-naphthoicacid, lactone form (Example 24), and3-hydroxymethyl-4-phenyl-7-[3-[4-(4-hydroxy-2β-methoxy-tetrahydro-pyranyl]benzyloxy]-2-naphthoicacid, lactone form (Example 25)

To a solution of the diol (77 mg) from Example 11 in MeOH (3 mL) and THF(3 mL) was added p-TSA (2 mg) and the resulting solution was stirred atr.t. 21 hr. The solvents were then evaporated under reduced pressure andthe residue was purified by flash chromatography (silica gel; CHCl₃/EtOAc, 75:25 to 60:40) to afford first the α-glycoside (Example 24) asa white solid; m.p. 179°-180° C., followed by the β-glycoside (Example25) as a white solid.

¹ H NMR (250 MHz, CDCl₃): δ1.69 (m, 1H), 1.82 (s, 1H), 1.94-2.13 (m,3H), 3.54 (s, 3H), 4.00-4.04 (m, 2H), 4.79 (dd, 1H), 5.20 (s, 2H), 5.23(s, 2H), 7.28-7.64 (m, 11H), 7.72 (d, 1H), 8.35 (s, 1H).

EXAMPLE 263-Hydroxymethyl-4-phenyl-7-[3-[4-(4-methyl)tetrahydropyranyl]benzyloxy]-2-naphthoicacid, lactone form

Following the procedure described in Example 1 but substituting3-[4-(4-methyl)tetrahydropyranyl]-benzyl bromide (Halide 9) for3-[4-(4-methoxy)tetrahydropyranyl]benzyl bromide, the title lactone wasobtained as a white solid.

¹ H NMR (250 MHz, CDCl₃): δ1.32 (s, 3H), 1.72-1.85 (m, 2H), 2.08-2.20(m, 2H), 3.63-3.85 (m, 4H), 5.23 (s, 2H), 5.26 (s, 2H), 7.30-7.60 (m,11H), 7.74 (d, 1H), 8.39 (s, 1H).

EXAMPLE 273-(1-Hydroxyethyl)-[3-[4-hydroxy)tetrahydropyranyl]benzyloxy]-4-phenyl-2-naphthoicacid, lactone form Step 1:7-benzyloxy-2,3-bis(hydroxymethyl)-4-phenylnaphthalene

To a suspension of LAH (3 g) in THF (50 mL) at 0° C., was added theanhydride from Lactone 1, Method B, Step 2 (6 g) in small portions. Theresulting reaction mixture was stirred at r.t. 2 hr then heated toreflux for 55 hr. After cooling to 0° C., an aqueous solution of 6N HClwas added dropwise until the aluminum salts dissolved. The mixture wasdiluted with EtOAc, washed with H₂ O (3×), brine, dried over MgSO₄, andthe solvent evaporated. The residue was swished in ether for 1 hr, thenfiltered to afford the title diol as a white solid.

Step 2:7-Benzyloxy-2-(tert-butyldiphenylsilyloxymethyl)-3-hydroxymethyl-4-phenylnaphthalene

To a solution of diol (1.02 g) from Step 1 in DMF (15 mL) was addedimidazole (410 mg) and t-BuPh₂ SiCl (790 μL) at r.t. After 1 hr thereaction mixture was diluted with Et₂ O, washed with H₂ O (3×), brine,dried over MgSO₄, and the solvent evaporated. The residue was purifiedby chromatography on silica gel using hexane/EtOAc 95:5 to give thetitle product.

Step 3:7-Benzyloxy-2-(tert-butyldiphenylsilyloxymethyl)-3-formyl-4-phenylnaphthalene

To a solution of alcohol (1.2 g) from Step 2 in CH₂ Cl₂ (25 mL) wasadded molecular sieves powder (1 g, flame dried) and PCC (1 g). After 40min, the reaction mixture was poured on a plug of SiO₂ (wet with Et₂ O),and eluted with Et₂ O. The solvent was evaporated to give the titleproduct.

Step 4:7-Benzyloxy-2-(tert-butyldiphenylsilyloxymethyl)-3-(1-hydroxyethyl)-4-phenylnaphthalene

To a solution of aldehyde (1.1 g) from Step 3 in THF (15 mL) at -78° C.,was added MeMgBr (1.4M PhMe-THF, 2.8 mL) dropwise. After 10 min, thebath was removed and the reaction mixture quenched with a saturatedsolution of NH₄ Cl. The reaction was diluted with Et₂ O, washed withsaturated NH₄ Cl solution, H₂ O, brine, dried over MgSO₄, and thesolvent evaporated to afford the title product as a foam.

Step 5:3-(1-Acetoxyethyl)-7-benzyloxy-2(tert-butyldiphenylsilyloxymethyl)-4-phenylnaphthalene

To a solution alcohol (300 mg) from Step 4 in Ac₂ O (2 mL) was addedpyridine (300 mL) and DMAP (2 mg). After 2 hr, the reaction mixture wasdiluted with Et₂ O, washed with H₂ O, a solution of CuSO₄, and thesolvent evaporated to give the title product which was used as such forthe next step.

Step 6:3-(1-Acetoxyethyl)-7-benzyloxy-2-hydroxymethyl-4-phenylnaphthalene

To a solution of the crude ether from Step 5 in THF (10 mL) at 0° C. wasadded HOAc, (4 drops) followed by n-Bu₄ NF (1M, THF, 1.4 mL). Thereaction mixture was stirred 2 hr at 0° C. then quenched with asaturated solution of NH₄ Cl and diluted with Et₂ O. The organic phasewas washed with H₂ O, brine, dried over MgSO₄, and the solventevaporated. The residue was purified by chromatography on silica gelusing hexane/EtOAc 7:3 to give the title product.

Step 7: 3-(1-Acetoxyethyl)-7-benzyloxy-4-phenyl-2-naphthoic acid

To a solution of alcohol (110 mg) from Step 6 in t-BuOH (6 mL) was addeda KH₂ PO₄ buffer solution (pH 7, 4 mL) and a solution of KMnO₄ (90 mg/2mL H₂ O). After 3 hrs at r.t., the reaction mixture was diluted withEtOAc and an aqueous solution of Na₂ SO₃. The mixture was then acidifiedto pH 2, the organic phase was separated, washed with H₂ O, brine, driedover MgSO₄ and evaporated to give the title product which was used assuch for the next step.

Step 8: 7-Benzyloxy-3-(1-hydroxyethyl)-4-phenyl-2-naphthoic acid,lactone form

To a solution of the crude acid (100 mg) from Step 7 in MeOH (3 mL) wasadded NaOMe (cat.). After 24 hr, the solvent was evaporated to dryness.The residue was dissolved in EtOAc (3 mL) and HCl 6N (2 drops). Thereaction mixture was stirred 20 min, washed with H₂ O (3×), brine, driedover MgSO₄, and the solvent evaporated to afford the title compound.

Step 9: 7-Hydroxy-3-(1-hydroxyethyl-4-phenyl-2-naphthoic acid, lactoneform

To a solution of the lactone (90 mg) from Step 8 in EtOAc was added 10%Pd/C (11 mg) and the reaction mixture was stirred under H₂ for 24 hr.The solution was filtered and the solvent evaporated to afford the titleproduct.

Step 10:3-(1-Hydroxyethyl)-[3-[4-hydroxy)tetrahydropyranyl]benzyloxy]-4-phenyl-2-naphthoicacid, lactone form

Following the procedure described in Example 1 but substituting7-hydroxy-3-(2-hydroxyethyl)-4-phenyl-2-naphthoic acid, lactone form,for 7-hydroxy-3-hydroxymethyl-4-phenyl-2-naphthoic acid lactone form,the title product was obtained as a glassy solid after purification bychromatography on silica gel using hexane/EtOAc/CH₂ Cl₂ (7:3:5). ¹ H NMR(250 MHz, CDCl₃): δ1.15 (d, 3H), 1.7 (m, 2H), 2.2 (m, 2H), 3.9 (m, 4H),5.25 (s, 2H), 5.7 (q, 1H), 7.27-7.7 (m, 12H), 8.35(s, 1H).

EXAMPLE 283-Hydroxymethyl-4-(4-fluorophenyl)-7-[3-[4-(4-hydroxy)tetrahydropyranyl]benzyloxy]-2-naphthoicacid lactone form

Following the procedure described in Example 18, but substituting7-hydroxy-3-hydroxymethyl-4-(4-fluorophenyl)-2-naphthoic acid, lactoneform (Lactone 2) for7-hydroxy-3-hydroxymethyl-4-(4-chlorophenyl)-2-naphthoic acid, lactoneform (Lactone 3), the title compound was obtained as a solid; m.p.167°-169° C. (dec).

EXAMPLE 293-Hydroxymethyl-4-phenyl-7-[3-[4-(4-ethyl)tetrahydropyranyl]benzyloxy]-2-naphthoicacid, lactone form

Following the procedure described in Example 1 but substituting3-[4-(4-ethyl)tetrahydropyranyl]benzyl bromide (Halide 10) for3-[4-(4-methoxy)tetrahydropyranyl]benzyl bromide, the title lactone wasobtained as a white solid; m.p. 157°-159° C.

EXAMPLE 303-Hydroxymethyl-4-(fluorophenyl)-7-[3-[4-(4-hydroxy)tetrahydropyranyl]benzyloxy]-2-naphthoicacid, lactone form

Following the procedure described in Example 18, but substituting7-hydroxy-3-hydroxymethyl-4-(2-fluorophenyl)-2-naphthoic acid, lactoneform (Lactone 5) for7-hydroxy-3-hydroxymethyl-4-(4-chlorophenyl)-2-naphthoic acid, lactoneform (Lactone 3), the title compound was obtained as a solid; m.p.194°-196° C.

EXAMPLE 313-Hydroxymethyl-4-(2-chlorophenyl)-7-[3-[4-(4-hydroxy)tetrahydropyranyl]benzyloxy]-2-naphthoicacid lactone form

Following the procedure described in Example 18, but substituting7-hydroxy-3-hydroxymethyl-4-(2-chlorophenyl)-2-naphthoic acid, lactoneform (Lactone 6) for7-hydroxy-3-hydroxymethyl-4-(4-chlorophenyl)-2-naphthoic acid, lactoneform (Lactone 3), the title compound was obtained as a solid; m.p.198°-200° C. (dec).

EXAMPLE 323-Hydroxymethyl-4-(3-methoxyphenyl)-7-[3-[4-(4-hydroxy)tetrahydropyranyl]benzyloxy]-2-naphthoicacid, lactone form

Following the procedure described in Example 18, but substituting7-hydroxy-3-hydroxymethyl-4-(3-methoxyphenyl)-2-naphthoic acid, lactoneform (Lactone 7) for7-hydroxy-3-hydroxymethyl-4-(4-chlorophenyl)-2-naphthoic acid, lactoneform (Lactone 3), the title compound was obtained as a solid; m.p.182°-184° C. (dec).

EXAMPLES 33 AND 343-Hydroxymethyl-4-phenyl-7-[3-[4-(4-hydroxy-2α-isopropyloxy)tetrahydropyranyl]benzyloxy]-2-naphthoicacid, lactone form (Example 33), and3-Hydroxymethyl-4-phenyl-7-[3-[4-(4-hydroxy-2β-isopropyloxy)tetra-hydropyranyl]benzyloxy]-2-naphthoicacid, lactone form (Example 34)

Following the procedure described in Examples 24 and 25, butsubstituting i-PrOH for MeOH, afforded the title compounds as a mixture.The two compounds were separated by flash chromatography (silica gel;CHCl₃ /EtOAc, 90:10 to 80:20) affording first the α-glycoside (Example33) followed by the β-glycoside (Example 34), both as white solids.

α-glycoside:

¹ H NMR (250 MHz, CDCl₃): δ1.19 (d, 3H), 1.33 (d, 3H), 1.74 (d, 1H),1.93 (d, 1H), 2.17 (dd, 1H), 2.29 (dd, 1H), 3.77 (dd, 1H), 4.04 (m, 1H),4.25 (td, 1H), 5.10 (s, 1H), 5.18 (d, 1H), 5.23 (s, 2H), 5.25 (s, 2H),7.30-7.75 (m, 12H), 8.38 (s, 1H).

β-Glycoside:

¹ H NMR (250 MHz, CDCl₃): δ1.19 (d, 3H), 1.26 (d, 3H), 1.68 (d, 1H),1.99-2.13 (m, 4H), 3.98-4.13 (m, 3H), 4.98 (dd, 1H), 5.20 (s, 2H), 5.24(s, 2H), 7.28-7.75 (m, 12H), 8.36 (s, 1H).

EXAMPLE 353-Hydroxymethyl-4-phenyl-7-[3-[3-(8-oxabicyclo[3:2:1]-oct-6-en-3α-ol)]benzyloxy]-2-naphthoicacid, lactone form

Following the procedure described in Example 1, but substituting Halide13 for 3-[4-(4-methoxy)-tetrahydropyranyl]benzyl bromide, the titlelactone was obtained as a white solid.

¹ H NMR (250 MHz, CDCl₃): δ1.92 (d, 2H), 2.55 (dd, 2H), 3.10 (s, 1H),4.94 (d, 2H), 5.22 (s, 2H), 5.26 (s, 2H), 6.62 (s, 2H), 7.29-7.60 (m,10H), 7.65 (s, 1H), 7.72 (s, 1H), 8.39 (s, 1H).

EXAMPLE 363-Hydroxymethyl-4-phenyl-7-[3-[3-(8-oxabicyclo[3.2.1]-octan-3δ-ol)]benzyloxy]-2-naphthoicacid, lactone form

Following the procedure described in Example 1 but substituting Halide14 for 3-[4-(4-methoxy)tetrahydropyranyl]benzyl bromide, the titlecompound was obtained as an off-white solid.

¹ H NMR (250 MHz, CDCl₃): δ1.81 (m, 2H), 1.98 (m, 3H), 2.40 (m, 4H),4.52 (m, 2H), 5.18 (s, 2H), 5.23 (s, 2H), 7.27-7.74 (m, 12H), 8.35 (s,1H).

EXAMPLE 373-Hydroxymethyl-4-phenyl-7-[3-[4-(hydroxy)tetrahydropyranyl]-4-methoxybenzyloxy]-2-naphthoicacid, lactone form

Following the procedure described in Example 18 but substituting3-[4-(4-hydroxy)tetrahydropyranyl]-4-methoxybenzyl bromide (Halide 15)for 3-[4-(4-hydroxy)tetrahydropyranyl]benzyl bromide (Halide 2) and7-hydroxy-3-hydroxymethyl-4-phenyl-2-naphthoic acid lactone form(Lactone 1) for 7-hydroxy-3-hydroxymethyl-4-(4-chlorophenyl)-2-naphthoicacid lactone form (Lactone 3), the title product was obtained as a whitesolid.

¹ H NMR (250 MHz, CDCl₃): δ1.95 (m, 2H); 2.2 (dt, 2H); 2.85 (m, 2H);3.95 (s, 3H); 4.0 (m, 2H); 5.15 (s, 2H); 5.25 (s, 2H); 7.0 (d, 1H); 7.3(dd, 1H); 7.4 (m, 5H); 7.55 (m, 3H); 7.75 (d, 1H); 8.4 (s, 1H).

EXAMPLE 383-(1-Hydroxy-1-methylethyl)-4-phenyl-7-[3-[4-(hydroxy)tetrahydropyranyl]benzyloxy]1-naphthoicacid, lactone form Step 1:3-Acetyl-7-benzyloxy-2-hydroxymethyl-4-phenylnaphthalene

To a heterogeneous solution of 500 mg of7-benzyloxy-2-hydroxymethyl-4-phenyl-3-naphthoic acid, lactone form(minor isomer obtained from Lactone 1, Method B, Step 3) in THF at -78°C. was added MeLi (1M, Et₂ O, 2mL). The reaction mixture was warmedslowly until the solution became homogeneous then quenched with asaturated NH₄ Cl solution. The organic phase was diluted with Et₂ O,washed with H₂ O, brine, dried over MgSO₄ and the solvent evaporated toafford the title compound used as such in the next step.

Step 2: 3-Acetyl-7-benzyloxy-4-phenyl-2-naphthoic acid

Following the procedure described in Example 27, Step 7, substituting3-(2-acetoxyethyl)-7-benzyloxy-2-hydroxymethyl-4-phenylnaphthalene for3-acetyl-7-benzyloxy-2-hydroxymethyl-4-phenylnaphthalene, the titleproduct was obtained and used as such in the next step.

Step 3: 7-Benzyloxy-3-(1-hydroxy-1-methylethyl)-4-phenyl-2-naphthoicacid, lactone form

To a solution of the acid (150 mg) from Step 2 in THF at -8° C. wasadded MeMgBr (1.4M, 0.8 mL) dropwise. After 2 hr, the reaction mixturewas quenched with 10% HCl and diluted with Et₂ O. After another 2 hr,the organic phase was extracted, washed with H₂ O, brine, dried overMgSO₄, and the solvent evaporated. The residue was purified bychromatography on silica gel using hexane/EtOAc/CH₂ Cl₂ (85:15:30) togive the title product.

Step 4: 7-Hydroxy-3-(1-hydroxy-1-methylethyl)-4-phenyl-2-naphthoic acid,lactone form

Following the procedure described in Lactone 1, Method A, Step 5, butsubstituting7-benzyloxy-3-(1-hydroxy-1-methylethyl)-4-phenyl-2-naphthoic acid,lactone form, for 7-benzyloxy-3-hydroxymethyl-4-phenyl-2-naphthoic acid,lactone form, the title product was obtained and used as such in thenext step.

Step 5:3-(1-Hydroxy-1-methylethyl)-4-phenyl-7-[3-[4-(4-hydroxy)tetrahydropyranyl]benzyloxy]-1-naphthoicacid, lactone form

Following the procedure described in Example 1, but substituting7-hydroxy-3-(1-hydroxy-1-methylethyl)-4-phenyl-2-naphthoic acid, lactoneform, for 7-hydroxy-3-hydroxymethyl-4-phenyl-2-naphthoic acid, lactoneform, the title product was obtained as a white foam. After purificationon flash chromatography (hexane/EtOAc, 1:1), the title compound wasobtained.

¹ H NMR (250 MHz, CDCl₃): δ1.49 (s, 6H), 1.7 (m, 2H), 2.22 (m, 2H), 3.93(m, 4H), 5.23 (s, 2H), 7.21-7.58 (m, 11H), 7.67 (s, 1H), 8.35 (s, 1H).

EXAMPLE 393-Hydroxymethyl-7-[3-[4-(4-hydroxy)tetrahydropyranyl]benzyloxy]-1-methoxy-4-phenyl-2-naphthoicacid, lactone form Step 1:3-[α,α-bis(Phenylthio)benzyl]-2-(3-benzyloxybenzoyl)butyrolactone

To a solution of the crude alcohol (10.8 g) from Lactone 1, Method E,Step 2, in CH₂ Cl₂ (150 mL) at 0° C. was added molecular sieves powder(flame dried, 10 g) followed by PCC (10.5 g) portion. The reactionmixture was stirred at r.t. for 1 hr then poured on a SiO₂ plug(prewashed with Et₂ O, and eluted with Et₂ O). The solvent wasevaporated and the residue purified by flash chromatography on silicagel using hexane/EtOAc 80:20 to give the title product.

Step 2:2-[α-Acetoxy(3-benzyloxybenzylidene)]-3[α,α-bis(phenylthio)benzyl]butyrolactone

To a solution of the ketone from Step 1 (1.91 g) in CH₂ Cl₂ (20 mL) wasadded Ac₂ O (1.5 mL), Et₃ N (2.3 mL) and DMAP (40 mg). The reactionmixture was stirred at r.t. for 18 hr then diluted with Et₂ O and asaturated solution of NH₄ Cl. The organic phase was extracted, washedwith H₂ O, brine, dried over MgSO₄, and the solvent evaporated to affordthe title product as a foam which was used as such in the next step.

Step 3: 1-Acetoxy-7-benzyloxy-3-hydroxymethyl-4-phenyl-2-naphthoic acid,lactone form

To a solution of acetoxy derivative (1.8 g) from Step 2, in TFA (8 mL)and thioanisole (2 mL) was stirred at 0° C. for 2 hr. The reactionmixture was diluted with Et₂ O, washed with H₂ O (3×), pH 7 buffersolution, brine, dried over MgSO₄, and the solvent evaporated. Theresidue was purified by chromatography on silica gel usinghexane/EtOAc/CH₂ Cl₂ (85:15:50) to give the title product.

Step 4: 7-Benzyloxy-1-hydroxy-3-hydroxymethyl-4-phenyl-2-naphthoic acid,lactone form

To a solution of lactone (320 mg) from Step 3, in MeOH/THF (5:1, 12 mL)was added a solution of NaOMe in MeOH (2 drops). After 18 hr thereaction mixture was acidified to pH 4 and the solvent evaporated. Theresidue was triturated in Et₂ O and filtered to afford the title productas a white solid.

Step 5:7-Benzyloxy-1-(t-butyldiphenylsilyloxy)-3-hydroxymethyl-4-phenyl-2-naphthoicacid, lactone form

To a solution of alcohol (160 mg) from Step 4, in CH₂ Cl₂ (10 mL) wasadded imidazole (60 mg) and t-BuPh₂ SiCl (150 μL). The reaction mixturewas stirred overnight then diluted with Et₂ O, washed with H₂ O andbrine, and dried over MgSO₄, and the solvent evaporated. The residue wastriturated in hexane and filtered to afford the title product as a whitesolid.

Step 6:1-(t-Butyldiphenylsilyloxy)-7-hydroxy-3-hydroxymethyl-4-phenyl-2-naphthoicacid, lactone form

To a solution of the lactone (120 mg) from Step 5, in EtOAc/CH₂ Cl₂(4:1) was added Pd(OH)₂ /C 20% (30 mg). The reaction mixture was stirredunder H₂ (balloon) for 36 hr then filtered and the solvent evaporated.The residue was triturated in Et₂ O and filtered to afford the titleproduct as a white solid.

Step 7:1-(t-Butyldiphenylsilyloxy)-3-hydroxymethyl-7-[3-[4-(4-hydroxy)tetrahydropyranyl]benzyloxy]-4-phenyl-2-naphthoicacid, lactone form

Following the procedure described in Example 7 but substituting1-(t-butyldiphenylsilyloxy)-7-hydroxy-3-hydroxymethyl-4-phenyl-2-naphthoicacid, lactone form from Step 6 for7-hydroxy-3-hydroxymethyl-4-phenyl-2-naphthoic acid, lactone form, thetitle product was obtained after purification on flash chromatography(hexane/EtOAc/CH₂ Cl₂, 85:15:40 to 65:35:40).

Step 8:1-Hydroxy-3-hydroxymethyl-7-[3-[4-(4-hydroxy)tetrahydropyranyl]benzyloxy]-4-phenyl-2-naphthoicacid, lactone form

To a solution of lactone (44 mg) from Step 7, in THF (5 mL) at 0° C. wasadded a n-Bu₄ NF solution (1M, 85 μL). The reaction mixture was stirredat r.t. for 1 hr then diluted with Et₂ O and H₂ O. The organic phase wasextracted, washed with H₂ O, brine, dried over MgSO₄, and the solventevaporated. The residue was triturated in Et₂ O and filtered to affordthe title product as a pale yellow solid.

Step 9:3-Hydroxymethyl-7-[3-[4-(4-hydroxy)tetrahydropyranyl]benzyloxy]-1-methoxy-4-phenyl-2-naphthoicacid, lactone form

To a solution of phenol (13 mg) from Step 8, in THF (2 mL) at 0° C. wasadded NaH (˜1.5 mg) followed by MeI (10 μL). The reaction mixture wasstirred at r.t. overnight then quenched with a pH 7 buffer solution anddiluted with Et₂ O. The organic phase was washed with H₂ O, brine, driedover MgSO₄, and the solvent evaporated. The residue was purified bychromatography on silica gel using hexane/EtOAc/CH₂ Cl₂ (7:3:5) to givethe title product as a white foam.

¹ H NMR (250 MHz, CDCl₃): δ1.65 (m, 2H), 2.15 (m, 2H), 3.85 (s, 3H),3.92 (m, 4H), 5.2 (s, 2H), 5.65 (s, 2H), 7.2 (dd, 1H), 7.32-7.63 (m,10H), 7.7 (s, 1H).

EXAMPLE 403-Hydroxymethyl-4-phenyl-7-[3-[4-(4α-hydroxy-2,2,6,6-tetramethyl)tetrahydrothiopyranyl]benzyloxy]-2-naphthoicacid, lactone form

Following the procedure described in Example 1, but substituting3-[4-(4α-hydroxy-2,2,6,6-tetramethyl)tetrahydrothiopyranyl]benzylchloride, (Halide 11) for 3-[4-(4-methoxy)tetrahydropyranyl]benzylbromide, and substituting Cs₂ CO₃ for K₂ CO₃, the title compound wasobtained as a white foam.

¹ H NMR (250 MHz, CDCl₃): δ1.3 (s, 6H); 1.7 (s, 6H); 2.0 (m, 5H);5.2-5.3 (2s, 4H); 7.2-7.7 (m, 12H); 8.4 (s, 1H).

EXAMPLE 413-Hydroxymethyl-4-phenyl-7-[3-[4-(4-hydroxy-2-oxo)tetrahydropyranyl]benzyloxy-2-naphthoicacid, lactone form

A mixture of the diol (152 mg) from Example 11 and Ag₂ CO₃ on celite(1.60 g; prepared as described in Tetrahedron, 31, 171, (1975)) inbenzene (25 mL) was refluxed for 4 hr. Filtration and evaporation of thefiltrate followed by flash chromatography (silica gel; CHCl₃ /EtOAc, 3:2yielded the title compound as a white solid.

¹ H NMR (250 MHz, CDCl₃): δ2.13-2.20 (m, 1H), 2.15 (s, 1H), 2.32-2.45(m, 1H), 2.87-3.05 (m, 2H), 4.42 (m, 1H), 4.75 (td, 1H), 5.24 (s, 2H),5.25 (s, 2H), 7.29-7.60 (m, 10H), 7.63 (s, 1H), 7.74 (d, 1H), 8.37 (s,1H).

What is claimed is:
 1. A compound of the formula: ##STR27## wherein: R¹and R⁵ are independently H, OH, lower alkyl, or lower alkoxy;R² is H,lower alkyl or together with R¹ forms a double bonded oxygen (═0); R³ isH, lower alkyl, or together with R¹ forms a carbon bridge of 2 or 3carbon atoms, said bridge optionally containing a double bond; each R⁴,R⁶ and R⁷ is independently H or lower alkyl; R⁸ is halogen, lower alkyl,or lower alkoxy; each R⁹ is independently H, halogen, lower alkyl, orlower alkoxy; R¹⁰ is H, halogen, lower alkyl, or lower alkoxy; X¹ is O,S, S(O), S(O)₂ or CH₂ ; X² is C(OR⁷) or C(R⁷); X³ is CH₂ O, OCH₂, or CH₂CH₂ ; ○ is phenyl or 1- or 2-naphthyl; m is 0, 1 or 2; n is 1;or thepharmaceutically acceptable salts thereof.
 2. A compound of claim 1 ofthe formula: ##STR28## wherein the substituents are:

    __________________________________________________________________________    EX.                                                                              R.sup.1                                                                             R.sup.3                                                                              R.sup.5                                                                           R.sup.8                                                                           X.sup.1                                                                           X.sup.2                                                                            X.sup.3                                      __________________________________________________________________________     1 H     H      H   H   O   C(OMe)                                                                             CH.sub.2 O                                    2 H     H      H   H   O   C(OMe)                                                                             OCH.sub.2                                     3 H     H      H   4-F O   C(OMe)                                                                             CH.sub.2 O                                    4 H     H      H   H   O   C(OH)                                                                              CH.sub.2 O                                    5 H     H      H   H   O   C(OEt)                                                                             CH.sub.2 O                                    6 H     H      H   H   CH.sub.2                                                                          C(OMe)                                                                             CH.sub.2 O                                    9 H     H      OH  H   O   C(OMe)                                                                             CH.sub.2 O                                   10 OH    H      H   H   O   C(OMe)                                                                             CH.sub.2 O                                   11 OH    H      H   H   O   C(OH)                                                                              CH.sub.2 O                                   12 H     H      OH  H   O   C(OH)                                                                              CH.sub.2 O                                   13 OH    H      OH  H   O   C(OH)                                                                              CH.sub.2 O                                   14 H     H      Me  H   O   C(OMe)                                                                             CH.sub.2 O                                   15 OH    H      OH  H   O   C(OMe)                                                                             CH.sub.2 O                                   16*                                                                              Me    Me     H   H   O   C(OH)                                                                              CH.sub.2 O                                   17*                                                                              Me    Me     H   H   O   C(OH)                                                                              CH.sub.2 O                                   18 H     H      H   4-Cl                                                                              O   C(OH)                                                                              CH.sub.2 O                                   19 H     H      H   4-OMe                                                                             O   C(OH)                                                                              CH.sub.2 O                                   20 Me    Me     H   H   O   C(OMe)                                                                             CH.sub.2 O                                   21 H     H      H   H   S   C(OH)                                                                              CH.sub.2 O                                   22 H     H      H   H   S(O)                                                                              C(OH)                                                                              CH.sub.2 O                                   23 H     H      H   H   S(O).sub.2                                                                        C(OH)                                                                              CH.sub.2 O                                   24**                                                                             OMe   H      H   H   O   C(OH)                                                                              CH.sub.2 O                                   25**                                                                             OMe   H      H   H   O   C(OH)                                                                              CH.sub.2 O                                   26 H     H      H   H   O   C(Me)                                                                              CH.sub.2 O                                   27 H     H      Me  H   O   C(OH)                                                                              CH.sub.2 O                                   28 H     H      H   4-F O   C(OH)                                                                              CH.sub.2 O                                   29 H     H      H   H   O   C(Et)                                                                              CH.sub.2 O                                   30 H     H      H   2-F O   C(OH)                                                                              CH.sub.2 O                                   31 H     H      H   2-Cl                                                                              O   C(OH)                                                                              CH.sub.2 O                                   32 H     H      H   3-OMe                                                                             O   C(OH)                                                                              CH.sub.2 O                                   33**                                                                             OCH(Me).sub.2                                                                       H      H   H   O   C(OH)                                                                              CH.sub.2 O                                   34**                                                                             OCH(Me).sub.2                                                                       H      H   H   O   C(OH)                                                                              CH.sub.2 O                                   35 (R.sup.1 R.sup.3) =                                                                 --CH═CH--                                                                        H   H   O   C(OH)                                                                              CH.sub.2 O                                   36 (R.sup.1 R.sup.3) =                                                                 --CH.sub.2 CH.sub.2 --                                                               H   H   O   C(OH)                                                                              CH.sub.2 O                                   __________________________________________________________________________     *cis and trans isomers                                                        **axial and equatorial isomers                                           


3. A compound of claim 1 of the formula: ##STR29## wherein thesubstituents are:

    ______________________________________                                        EX.   R.sup.1 R.sup.2                                                                              R.sup.3                                                                            R.sup.4                                                                            R.sup.5                                                                            R.sup.6                                                                            R.sup.9                                                                            R.sup.10                                                                           X.sup.1                    ______________________________________                                        37    H       H      H    H    H    H    H    4-   O                                                                        OMe                             38    H       H      H    H    Me   Me   H    H    O                          39    H       H      H    H    H    H    1-   H    O                                                                   OMe                                  40    Me      Me     Me   Me   H    H    H    H    S                          41    (R.sup.1                                                                              ═O H    H    H    H    H    H    O                                R.sup.2) =                                                              ______________________________________                                    


4. The following compounds of claim1:3-Hydroxymethyl-4-phenyl-7-{3-[4-[(4-methoxy)tetrahydropyranyl]benzyloxy}-2-naphthoicacid, lactone form;3-Hydroxymethyl-4-phenyl-7-{3-[4-(4-methoxy)tetrahydropyranyl]phenoxymethyl}-2-naphthoicacid, lactone form;3-Hydroxymethyl-4-(4-fluorophenyl)-7-{3-[4-(4-methoxy)tetrahydropyranyl]benzyloxy}-2-naphthoicacid, lactone form;3-Hydroxymethyl-4-phenyl-7-{3-[4-(4-hydroxy)tetrahydropyranyl]benzyloxy}-2-naphthoicacid, lactone form;3-Hydroxymethyl-4-phenyl-7-{3-[4-(4-ethoxy)tetrahydropyranyl]benzyloxy}-2-naphthoicacid, lactone form;3-Hydroxymethyl-4-phenyl-7-{3-(1-methoxycyclohexyl)benzyloxy}-2-naphthoicacid, lactone form;3-Formyl-4-phenyl-7-{3-[4-(4-methoxy)tetrahydropyranyl)benzyloxy}-2-naphthoicacid, lactone form;3-Hydroxymethyl-4-phenyl-7-[3-[4-(2,4-dihydroxy)tetrahydropyranyl]benzyloxy]-2-naphthoicacid, lactone form;3-Formyl-4-phenyl-7-[3-[4-(4-hydroxy)tetrahydropyranyl[benzyloxy]-2-naphthoicacid, lactone form;3-Hydroxymethyl-4-phenyl-7-[3-[4-(4α-hydroxy-2,6-dimethyl)tetrahydropyranyl]benzyloxy]-2-naphthoicacid, lactone form;3-Hydroxymethyl-4-phenyl-7-[3-[4-(4β-hydroxy-2,6-dimethyl)tetrahydropyranyl]benzyloxy]-2-naphthoicacid lactone form;3-Hydroxymethyl-4-(4-chlorophenyl)-7-[3-[4-(4-hydroxy)tetrahydropyranyl]benzyloxy]-2-naphthoicacid, lactone form;3-Hydroxymethyl-4-(4-methoxyphenyl)-7-[3-[4-hydroxy)tetrahydropyranyl]benzyloxy]-2-naphthoicacid, lactone form;3-Hydroxymethyl-4-phenyl-7-[3-[4-(4α-methoxy-2,6-dimethyl)tetrahydropyranyl]benzyloxy]-2-naphthoicacid, lactone form;3-Hydroxymethyl-4-phenyl-7-[3-[4-(4-hydroxy)tetrahydrothiopyranyl]benzyloxy]-2-naphthoicacid, lactone form;3-Hydroxymethyl-4-phenyl-7-[3-[4-(4-hydroxy-S-oxo)tetrahydrothiopyranyl]benzyloxy]-2-naphthoicacid, lactone form;3-Hydroxymethyl-4-phenyl-7-[3-[4-(4-hydroxy-S,S-dioxo)tetrahydrothiopyranyl]benzyloxy]-2-naphthoicacid, lactone form;3-Hydroxymethyl-4-phenyl-7-[3-[4-(4-hydroxy-2α-methoxy)tetrahydropyranyl]benzyloxy]-2-naphthoicacid, lactone form;3-Hydroxymethyl-4-phenyl-7-[3-[4-(4-hydroxy-2β-methoxy)tetrahydropyranyl]benzyloxy]-2-naphthoicacid, lactone form;3-Hydroxymethyl-4-phenyl-7-[3-[4-(4-methyl)tetrahydropyranyl]benzyloxy]-2-naphthoicacid, lactone form;3-(1-Hydroxyethyl)-[3-[4-hydroxy)tetrahydropyranyl]benzyloxy]-4-phenyl-2-naphthoicacid, lactone form;3-Hydroxymethyl-4-(4-fluorophenyl)-7-[3-[4-(4-hydroxy)-tetrahydropyranyl]benzyloxy]-2-naphthoicacid lactone form;3-Hydroxymethyl-4-phenyl-7-[3-[4-(4-ethyl)tetrahydropyranyl]benzyloxy]-2-naphthoicacid, lactone form;3-Hydroxymethyl-4-(fluorophenyl)-7-[3-[4-(4-hydroxy)tetrahydropyranyl]benzyloxy]-2-naphthoicacid, lactone form;3-Hydroxymethyl-4-(2-chlorophenyl)-7-[3-[4-(4-hydroxy)tetrahydropyranyl]benzyloxy]-2-naphthoicacid lactone form;3-Hydroxymethyl-4-(3-methoxyphenyl)-7-[3-[4-(4-hydroxy)tetrahydropyranyl]benzyloxy]-2-naphthoicacid, lactone form;3-Hydroxymethyl-4-phenyl-7-[3-[4-(4-hydroxy-2α-isopropyloxy)tetrahydropyranyl]benzyloxy]-2-naphthoicacid, lactone form;3-Hydroxymethyl-4-phenyl-7-[3-[4-(4-hydroxy-2β-isopropyloxy)tetrahydropyranyl]benzyloxy]-2-naphthoicacid, lactone form;3-Hydroxymethyl-4-phenyl-7-[3-[3-(8-oxabicyclo[3.2.1]oct-6-en-3α-ol)]benzyloxy]-2-naphthoicacid, lactone form;3-Hydroxymethyl-4-phenyl-7-[3-[3-(8-oxabicyclo[3.2.1]octan-3α-ol)]benzyloxy]-2-naphthoicacid, lactone form;3-Hydroxymethyl-4-phenyl-7-[3-[4-(hydroxy)tetrahydropyranyl]-4-methoxybenzyloxy]-2-naphthoicacid, lactone form;3-(1-Hydroxy-1-methylethyl)-4-phenyl-7-[3-[4-(4-hydroxy)tetrahydropyranyl]benzyloxy]-1-naphthoicacid, lactone form;3-Hydroxymethyl-7-[3-[4-(4-hydroxy)tetrahydropyranyl]benzyloxy]-1-methoxy-4-phenyl-2-naphthoicacid, lactone form;3-Hydroxymethyl-4-phenyl-7-[3-[4-(4α-hydroxy-2,2,6,6-tetramethyl)tetrahydrothiopyranyl]benzyloxy]-2-naphthoicacid, lactone form; or3-Hydroxymethyl-4-phenyl-7-[3-[4-(4-hydroxy-2-oxo)tetrahydropyranyl]benzyloxy-2-naphthoicacid, lactone form.
 5. A pharmaceutical composition comprising atherapeutically effective amount of a compound of claim 1 and apharmaceutically acceptable carrier.
 6. A method of preventing thesynthesis, the action, or the release of SRS-A or leukotrienes in amammal which comprises administering to said mammal an effective amountof a compound of claim
 1. 7. The method of claim 6 wherein the mammal isman.
 8. A method of treating asthma in a mammal comprising administeringto a mammal in need of such treatment a therapeutically effective amountof a compound of claim
 1. 9. A method of treating inflammatory diseasesof the eye in a mammal which comprises administering to a mammal in needof such treatment a therapeutically effective amount of a compound ofclaim
 1. 10. The method of claim 9 wherein the mammal is man.